Infusion of human mesenchymal stromal cells during normothermic machine perfusion of porcine kidneys: a randomized, blinded, preclinical study

Background Kidney transplantation from donation after circulatory death (DCD) donors is increasingly used but remains associated with warm ischemic injury. Normothermic machine perfusion (NMP) enables functional assessment and therapeutic interventions. Mesenchymal stromal cells (MSCs) display immunomodulatory and regenerative properties, yet their translational efficacy during NMP remains unclear. Methods In a porcine model, six pairs of kidneys subjected to 30 minutes of warm ischemia followed by 3 hours of static cold storage underwent 6 hours of NMP. In each pair, one kidney randomly received an intra-arterial injection of placebo, while the contralateral kidney received 10 million clinical-grade human bone marrow–derived MSCs (hMSCs). Perfusion characteristics, glomerular filtration, tissue injury, and inflammatory markers were assessed. Results hMSC infusion during NMP was technically feasible and hemodynamically well tolerated, with no adverse effects on perfusion stability. Perfusion parameters, urine output, and creatinine/iohexol clearance showed no significant differences between groups. NGAL and cytokines levels increased during perfusion, but hMSCs did not alter their dynamics. Conclusions Intra-arterial delivery of clinical grade hMSCs during NMP was safe but did not improve renal function or reduce histological injury. These results highlight the challenges of achieving MSC engraftment during ex situ perfusion and highlight the need for refined strategies such as repeated dosing, prolonged perfusion, or extracellular vesicle therapy. Despite the negative findings, this study presents a highly translational large-animal model, supporting further investigation of MSC-based therapies in human kidneys discarded for transplantation.