Organ-specific responses during brain death: increased aerobic metabolism in the liver and anaerobic metabolism with decreased perfusion in the kidneys

A C Van Erp,M Pedersen,H G D Leuvenink,J G M Burgerhof,J C Wolters,C Laustsen,P J Ottens,N R Jespersen,J Ciapaite,R Nørregaard,D Hoeksma,R A Rebolledo,H E Bøtker,B Jespersen

doi:10.1038/s41598-018-22689-9

Abstract

Hepatic and renal energy status prior to transplantation correlates with graft survival. However, effects of brain death (BD) on organ-specific energy status are largely unknown. We studied metabolism, perfusion, oxygen consumption, and mitochondrial function in the liver and kidneys following BD. BD was induced in mechanically-ventilated rats, inflating an epidurally-placed Fogarty-catheter, with sham-operated rats as controls. A 9.4T-preclinical MRI system measured hourly oxygen availability (BOLD-related R2*) and perfusion (T1-weighted). After 4 hrs, tissue was collected, mitochondria isolated and assessed with high-resolution respirometry. Quantitative proteomics, qPCR, and biochemistry was performed on stored tissue/plasma. Following BD, the liver increased glycolytic gene expression (Pfk-1) with decreased glycogen stores, while the kidneys increased anaerobic- (Ldha) and decreased gluconeogenic-related gene expression (Pck-1). Hepatic oxygen consumption increased, while renal perfusion decreased. ATP levels dropped in both organs while mitochondrial respiration and complex I/ATP synthase activity were unaffected. In conclusion, the liver responds to increased metabolic demands during BD, enhancing aerobic metabolism with functional mitochondria. The kidneys shift towards anaerobic energy production while renal perfusion decreases. Our findings highlight the need for an organ-specific approach to assess and optimise graft quality prior to transplantation, to optimise hepatic metabolic conditions and improve renal perfusion while supporting cellular detoxification.

Highlights

The shortage of donor organs suitable for transplantation remains a major healthcare challenge
Brain death (BD) is the result of increased intracranial pressure (ICP), which leads to progressive ischemia of the cerebrum, brain stem, and spinal cord
Considering the neuro-endocrine dysregulation, as well as haemodynamic impairment and inflammation during BD, it is conceivable that metabolism is altered during BD and that this influences the quality of transplantable organs

Summary

Introduction

The shortage of donor organs suitable for transplantation remains a major healthcare challenge. Similar results in the myocardium of brain-dead pigs point towards increased anaerobic metabolism in combination with decreased ATP levels[20] These studies suggest that the observed metabolic changes are caused either by impaired oxygen utilization due to a primary metabolic (i.e. mitochondrial) impairment or alternatively, by impaired oxygen delivery due to changes in tissue perfusion[21]. A recent publication shows that mitochondrial and metabolic pathways are most pre-dominantly affected following BD27 Together, this suggests that exploration of metabolic changes during BD and possible underlying causes, will provide insights into organ-specific metabolic alterations prior to preservation and might justify (pre)conditioning of grafts prior to transplantation. We assessed mitochondrial function by measuring in vitro mitochondrial respiration as well as mitochondrial proteomics after 4 hrs of BD

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