Cross-species transcriptomic comparison of human versus murine donor kidneys in circulatory death (DCD) or brain death (DBD)

Introduction:
This study compares the transcriptome of pre-implantation human kidney biopsies and murine kidneys to assess the relevance of these animal models of donors in brain death (DBD) versus circulatory death (DCD).

Methods:
We analyzed 10 human preimplantation kidney biopsies (5 DCD and 5 DBD) and 16 rat kidneys (9 DCD and 7 DBD) with matched criteria (14h cold ischemia; <10h brain death (DBD) or 20 minutes warm ischemia (DCD)). Samples were subjected to high-throughput RNA sequencing (Illumina®). Differential expression analysis followed by pathway enrichment analysis were performed using DESeq2 in R (version 4.4.0) and Ingenuity Pathway Analysis (Qiagen®).

Results:
Principal component analysis (PCA) showed a separation between the DBD and DCD groups, in both humans and rats. In humans, PC1 and PC2 accounted for 32% and 20% of total variability respectively. Murine results showed 60% and 9% for PC1 and 2. In humans, 503 genes were down-regulated and 338 up-regulated in DBD vs DCD. In rats, we had 2144 down-regulated genes and 1950 upregulated. Pathway enrichment analyses showed that 5 of the 10 major pathways enriched in each model were common to both species, including acute response signaling, IL10, IL17 and IL6 signaling, and JAK kinase signaling. The “Tox and Functions” analysis revealed a common positive enrichment for “mesangial cell proliferation” and “proximal tubular toxicity” in human and murine DBD vs DCD biopsies.

Conclusion:
Our rat models mimic the transcriptomic characteristics of human biopsies from DBD and DCD donors. This concordance makes it possible to use these animal models to study the mechanisms of per-transplant lesions and test preconditioning strategies suited to the type of donor.