Date: Monday, June 3, 2019
Session Time: 2:30pm-4:00pm
Presentation Time: 3:06pm-3:18pm
Location: Room 313
*Purpose: Delayed graft function (DGF) is the manifestation of ischemia reperfusion injury (IRI) in the context of kidney transplantation. Despite clear preclinical successes, a proven protective therapy for clinical IRI remains missing. This paradox is thought to mainly reflect profound methodological problems in translating experimental (animal) findings to the clinical context. Our previous work identified failing recovery of oxidative phosphorylation as the discriminative feature of future DGF in the context of human kidney transplantation. This observation points to a metabolic basis for clinical IRI. To test this hypothesis, we performed an in-depth metabolomic analysis of the early reperfusion phase during clinical kidney transplantation.
*Methods: This study combines data obtained from pre- and post (t=45 min) reperfusion renal tissue biopsies, with sequential arterio-venous blood sampling over the transplanted graft. Three study groups were defined on basis of clinical outcome: grafts from living donors (reference), and deceased donor grafts with (+DGF) and without (-DFG). Magic angle NMR was used for tissue analysis, and MS-based platforms for organic acids, acylcarnitine, amino acids and purines for the arterio-venous plasma samples.
*Results: 1-year graft survival was 100%. Integration of the metabolic data identified a profile that is fully discriminatory for future DGF. This metabolome is characterized by ongoing tissue damage, and post-reperfusion ATP/GTP catabolism, indicated by persistent (hypo)xanthine production. Failing recovery of high-energy phosphates occurred despite activated glycolysis, fatty acid oxidation, glutaminolysis and autophagy, and was related to a defect at the level of the oxoglutarate complex in the Krebs cycle.
*Conclusions: This study shows that in human organ ischemia and reperfusion, functional tissue damage (future DGF) is preceded by an instantaneous metabolic collapse at the level of the Krebs cycle. The observed metabolic defects fully contrast with those reported for rodents, and therefore providing a rationale for the poor translatability of preclinical findings. Efforts to quench clinical IRI should focus on the preservation of metabolic competence, either by preserving the integrity of the Krebs cycle and/or by recruiting metabolic rescue pathways.
To cite this abstract in AMA style:Lindeman J. An Immediate and Persistent Post-Reperfusion Metabolic Collapse Precedes Delayed Graft Function (DGF) [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/an-immediate-and-persistent-post-reperfusion-metabolic-collapse-precedes-delayed-graft-function-dgf/. Accessed November 25, 2020.
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