A Metabolic Index of Ischemic Injury for Perfusion-Recovery of Cadaveric Rat Livers

Abstract

With over 110,000 patients waiting for organ transplantation, the current crisis in organ transplantation is based on a lack of donors after brain-death (DBD). A very large alternative pool of donor organs that remain untapped are the donors after cardiac death (DCD), recovered after cardiac activity has ceased and therefore sustained some ischemic injury. Machine perfusion has been proposed as a novel modality of organ preservation and treatment to render such cadaveric organs, and in particular livers, transplantable. Two key issues that remain unaddressed are how to assess whether a DCD liver is damaged beyond repair, and whether machine perfusion has rendered an injured organ sufficiently viable for transplantation. In this work, we present a metabolic analysis of the transient responses of cadaveric rat livers during normothermic machine perfusion (NMP), and develop an index of ischemia that enables evaluation of the organ ischemic injury level. Further, we perform a discriminant analysis to construct a classification algorithm with >0.98 specificity to identify whether a given perfused liver is ischemic or fresh, in effect a precursor for an index of transplantability and a basis for the use of statistical process control measures for automated feedback control of treatment of ischemic injury in DCD livers. The analyses yield an index based on squared prediction error (SPE) as log(SPE) >1.35 indicating ischemia. The differences between metabolic functions of fresh and ischemic livers during perfusion are outlined and the metabolites that varied significantly for ischemic livers are identified as ornithine, arginine, albumin and tyrosine.

Metabolomic Profiling for Identification of Potential Biomarkers in the Protective Effects of Modified Sinisan against Liver Injury in Dimethylnitrosamine Treated Rats

“…It has been demonstrated by other investigators that large quantities of phenylalanine and tyrosine were detected in patients with liver injury and these amino acids were specifically released in the patients of liver injury. 21,22) Significant correlations were observed between phenylalanine and tyrosine concentrations and total bilirubin levels and albumin levels. Serum phenylalanine and tyrosine concentrations correlated well with imaging and laparotomy findings of liver injury.…”

The promise of organ and tissue preservation to transform medicine

“…For example, it has been proposed by the National Heart Lung and Blood Institute and found by other studies that many hearts that would provide substantial survival benefits to patients are going unused, largely owing to a lack of reliable methods to assess their suitability for transplantation 79,92 . By allowing organ function to be observed after procurement, perfusion platforms are enabling the investigation of new biomarkers that predict organ health and transplantability 93–96 .…”

Graft Reconditioning With Nitric Oxide Gas in Rat Liver Transplantation From Cardiac Death Donors

“…A few studies have reported reclamation of DCD grafts exposed to 60-min warm ischemia. Peaks et al and Tolboom et al successfully rescued almost all transplants that underwent 60-min warm ischemia by normothermic extracorporeal perfusion (2,31). In terms of survival, after 60-min warm ischemia, VSOP-NO appeared to be inferior to machine perfusion.…”