Cross-species transcriptomic comparison of human versus murine donor kidneys after circulatory death or brain death

Background:
This study compares the transcriptome of pre-implantation human kidney biopsies and murine kidneys
to assess the relevance of rat models of kidney donors after brain death (DBD) or 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 (i.e. 14-hour cold ischemia; <10h post brain death (DBD) or
20 minutes of 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 data showed 60% and 9% for PC1 and 2, respectively. 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 compared to DCD biopsies.
Conclusions:
Our rat models mimic the transcriptomic characteristics of human biopsies from DBD and DCD donors.
This concordance makes these animal models useful to study the mechanisms of per-transplant lesions
and test preconditioning strategies suited to each type of donor.