Background: Strategies to improve long term renal allograft survival have been directed to recipient dependent mechanisms of renal allograft injury. In contrast, no such efforts have been made to optimize organ quality in the donor. In order to get insight into the deleterious gene pathways expressed at different time points during deceased kidney transplantation, transcriptomics was performed on kidney biopsies from a large cohort of deceased kidney transplants. Methods: A total of 554 kidney biopsies were taken from living and deceased donor kidneys at donation, after cold ischemia and after reperfusion. Transcriptomics by means of whole genome micro-array analyses followed by functional pathway analyses was performed. Results: Oxidative stress and complement- and coagulation pathways were uncovered as potential pathways for intervention in deceased donors. No genes were found to be differentially expressed between donation and cold ischemia. After reperfusion, pathways related to oxidative stress, NOD-like signalling, MAPK, cytokine-cytokine receptor, complement- and-coagulation and chemokines were enriched in kidneys from deceased organ donors. Pathways related to prolonged and worsening deprivation of oxygen were associated with delayed graft function of DCD grafts. Conclusions: The present study reveals oxidative stress and enrichment of complement and coagulation pathways in deceased donor kidneys. Future intervention therapies to optimize donor organ quality and prolong allograft survival should target oxidative stress and innate immune activation in the donor.
Overall design
Total RNA was isolated from kidney biopsies. Biopsies were taken from deceased brain-dead kidney donors (n=81) and deceased cardiac dead donors (n=37) before organ retrieval. From another transplant cohort, kidney biopsies were taken after cold ischemia and after reperfusion of a brain-dead donor kidney (n=67 paired, 43-38 unpaired) or cardiac-dead donor kidney (n=29 paired, 24-35 unpaired). Living donors kidney biopsies (n=37) and paired living reperfusion biopsies (n=34) served as controls. Three timepoints: T1 = Kidney biopsy taken before organ retrieval in deceased donors T2 = After cold ischemia T3 = 60 minutes after reperfusion
Less...
More...