Impact of Normothermic Perfusion enriched with Mesenchymal Stromal Cells on Renal Ischemia/Reperfusion Injury

Kidney transplantation represents the gold standard treatment for end-stage renal disease,
offering superior survival and quality of life compared to all forms of dialysis. However, the
persistent organ shortage compels the transplant community to broaden donor acceptance
criteria — particularly to donation after circulatory death (DCD) donors and extended criteria
donors (ECD) — whose grafts are especially vulnerable to ischemia-reperfusion injury (IRI).
These injuries, which are central to early graft dysfunction, increase the risk of delayed graft
function (DGF).
Normothermic machine perfusion (NMP) represents a major advance in organ preservation:
by maintaining the kidney at physiological temperature with an oxygenated, metabolically
enriched perfusate, it restores active aerobic metabolism, enables dynamic assessment of
graft viability, and opens a window for therapeutic intervention. In parallel, mesenchymal
stromal cells (MSCs) have emerged as a promising therapeutic platform owing to their
immunomodulatory and regenerative properties, mediated primarily through paracrine
signalling via their secretome.
This thesis explores the combination of these two technologies within a four-step translational
research programme. First, a systematic review with meta-analysis was conducted to provide
a rigorous overview of stem cell-based therapies administered during ex vivo perfusion of
kidney grafts. Building on this foundation, a porcine model of simultaneous NMP of both
kidneys from the same donor was developed and validated, enabling paired intra-animal
comparisons and eliminating inter-individual variability. This model then served as a platform
to evaluate intra-arterial delivery of clinical-grade human MSCs during NMP of ischaemic
porcine kidneys. Finally, this strategy was translated to human kidneys declined for
transplantation.
This work establishes the scientific, technical, and translational foundations of intra-arterial
clinical-grade hMSC delivery during NMP as a novel potential strategy for attenuating IRI in
deceased-donor kidney transplantation and paves the way for eventual clinical application.