Exploring ex vivo modulation of fibrosis in discarded human donor kidneys
IntroductionEarly-onset fibrosis limits kidney transplant success. Normothermic machine perfusion (NMP) offers a platform for targeted drug delivery directly to isolated organs, minimizing systemic effects. This study evaluated the long-term anti-fibrotic efficacy and safety of galunisertib in discarded human kidneys perfused ex vivo. MethodsTwelve discarded human kidneys underwent 4 hours of oxygenated hypothermic perfusion followed by 6 hours of NMP with galunisertib or vehicle (n=6). Precision-cut kidney slices (PCKS) were then cultured for 48 hours with either continued or discontinued galunisertib exposure. Endpoints included fibrosis-related mRNA expression and pharmacokinetics. ResultsGalunisertib did not negatively affect renal function during NMP. Continued exposure in PCKS significantly attenuated fibrosis-related mRNA expression, including SERPINE1 (p=0.0046), TGF-{beta} (p=0.0168), FN1 (p=0.0269) and ACTA2 (p=0.0014) after 48 hours. The discontinuation of treatment did not exhibit the same anti-fibrotic effects. ConclusionGalunisertib was safely administered during NMP and steadily excreted via the urine. NMP showed to be a promising platform for safe targeted anti-fibrotic therapy delivery, offering potential to improve graft quality. When treatment was sustained, galunisertib induced a modest reduction in fibrosis-related mRNA expression over 48 hours of tissue incubation. Further studies are needed to optimize delivery strategies and evaluate the impact of prolonged therapeutic exposure.