RAP100: Examining the mechanisms involved in the potential down-regulation of brain-stem death induced proinflammatory responses by simvastatin
This project builds on an NIHR-funded HTA trial, SIGNET, a study randomising organ donors to statin treatment or control. The trial started in September 2021 and is the largest organ donor intervention study anywhere in the world. The mechanistic arm, the subject of this study, is NIHR-EME funded and utilises the QUOD biobank to access to samples from organ donors in the study. This study is led by Professors Simi Ali and John Dark at Newcastle University.
Statins are 3-hydroxy-3-methyl coenzyme A reductase inhibitors, with many pleiotropic effects, which may modulate the inflammatory processes in brain-stem dead donors. The hypothesis is that a statin within protocolised care after diagnosis of brain-stem death improves outcomes in patients undergoing transplantation. The study aims to explore the underlying mechanistic pathways that confer statin induced organ protection.
Main objectives are:
- Examine whether statin administration reduces donor inflammation by cytokine modulation and if time of administration has an effect.
- Determine whether inflammatory sub-phenotypes exist in the donor population and whether these sub-phenotypes are associated with clinical outcomes (number of organs utilised per donor)
- Examine gene expression profiles in heart tissue biopsies after donor statin administration.
- Examine long-term effects of statin treatment in a selected cohort of transplant patients.
Experiments are being carried out with data already collected in the National Transplant Database and biological samples from the QUOD programme. No extra data or blood samples are needed from recipients/donors.
Serum samples are obtained before the drug is administered, but after brain death, and then at organ retrieval from donors in both arms of the study. These samples are being tested for cytokines, to detect whether there is a significant difference in cytokine expression between the treatment groups and to study the effect of time of administration on statin-induced cytokine changes. Secondly, these cytokine data along with baseline data will be used in a latent class analysis (LCA), without consideration to outcome, to identify donor sub-phenotypes. Post-LCA discovery, we will study whether sub-phenotypes correlate with distinct clinical outcomes.
In order to identify genes, which are involved in statin induced anti-inflammatory effects, the tissue samples from donors which show anti-inflammatory response will be used to identify the differentially regulated genes in pairwise comparisons. Finally, in order to evaluate whether initial statin administration has long term anti-inflammatory effects in patients, analysis will be carried out in a smaller cohort of local transplant patients.
This will potentially allow us to identify organ donors based on cytokine and gene expression who are more likely to benefit from statin intervention. Thus, leading to larger organ pool and better function in recipients.