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Published on: August 15, 2022
Functional Implications of Biochemical and Molecular Characteristics of Donation After Circulatory Death Livers
Ryota Masuzaki1, Hui Yu2, Philip Kingsley3
1The Transplant Center, Department of Surgery, Vanderbilt University Medical Center, Nashville, TN.
Insights
Lower adenosine triphosphate (ATP) levels in livers from circulatory death donors (DCD) immediately after cold perfusion correlate with ischemic injury. Gene expression changes in DCD livers may offer insights for improving transplant outcomes.
Area of Science:
- Transplantation immunology
- Organ preservation
- Biochemistry
Background:
- Livers from donors after circulatory death (DCD) have lower graft and patient survival rates than those from brain dead donors (DBD).
- A method to predict DCD liver function is needed to improve organ utilization and patient outcomes.
- Ischemic time in DCD donors may cause immediate biochemical and molecular changes affecting graft function.
Purpose of the Study:
- To identify biochemical and molecular markers in DCD livers that predict post-transplant function.
- To investigate the impact of ischemic time on DCD liver viability.
- To compare DCD and DBD liver tissue immediately after cold perfusion and during cold storage.
Main Methods:
- Biopsies of DCD and DBD livers were analyzed immediately after cold perfusion and during cold storage.
- Biochemical analysis included adenosine triphosphate (ATP) and other metabolites.
- Molecular analysis involved transcriptional profiling using high-throughput sequencing.
- Metabolite levels were correlated with post-transplant aspartate aminotransferase (AST) levels.
Main Results:
- DCD liver samples had significantly lower ATP and adenosine diphosphate (ADP) levels immediately post-perfusion compared to DBD samples.
- Lower ATP levels correlated with higher peak AST levels in recipients, indicating greater ischemic injury.
- 470 genes were differentially expressed in DCD livers, with upregulation in inflammation/immunity and downregulation in translation.
- No significant transcriptional changes were observed during cold storage.
Conclusions:
- ATP content post-perfusion is a reliable indicator of ischemic injury in DCD livers.
- Transcriptional profiling reveals biological pathways relevant for enhancing DCD liver function.
- Messenger RNA (mRNA) levels during cold storage are not prognostic due to transcriptional inactivity.
Unlabelled:
In aggregate, livers donated after circulatory death (DCD) provide lower rates of graft and patient survival compared to brain dead donors (DBD). A method to identify DCD livers likely to perform well would lead to better decision-making regarding which livers to use and which to discard and is an important unmet clinical need. We hypothesized that the ischemic time between extubation and cold perfusion in the donor leads to immediate and unique biochemical and molecular changes that could be used to predict subsequent function.
Methods:
Biopsies from normal perfused liver, immediately after cold perfusion during DCD or DBD liver procurement, and during subsequent cold storage were analyzed and compared. Biochemical analysis included adenosine triphosphate (ATP), adenosine diphosphate, adenosine monophosphate, hypoxanthine, xanthine, inosine, nicotinamide adenine dinucleotide, and flavin adenine dinucleotide. Levels of these metabolites were compared to peak posttransplant aspartate aminotransferase as a marker of ischemic injury. Molecular analysis was performed by transcriptional profiling using high throughput sequencing.
Results:
Immediately after cold perfusion in the donor, biochemical analysis revealed lower levels of ATP and adenosine diphosphate in DCD versus DBD liver samples (P < 0.01 in both cases). The ATP levels showed high negative correlation with peak aspartate aminotransferase levels in recipients (P = 0.029). Four hundred seventy genes showed differential expression in DCD but not DBD samples immediately after cold perfusion compared with normal liver samples. Upregulated genes function in inflammation and immunity, whereas downregulated genes function in translation. During cold storage, samples were transcriptionally inactive with no consistent changes in messenger RNA expression.
Conclusion:
The ATP content of liver samples taken immediately postperfusion correlates with ischemic injury. Transcriptional profiling identifies biological process that may be relevant for enhancing function in DCD liver transplantation. Transcriptional inactivity of cold stored samples suggests messenger RNA levels over time are unlikely to provide prognostic data.
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