Targeted delivery of galunisertib using machine perfusion reduces fibrogenesis in an integrated ex vivo renal transplant and fibrogenesis model

Abstract

AbstractBackground and PurposeFibrosis in kidney allografts is a major post‐transplant complication that contributes to graft failure. Lately, multiple potent inhibitors of fibrosis‐related pathways have been developed such as galunisertib, an inhibitor of the transforming growth factor‐beta (TGF‐β/TGFβ1) signalling pathway. This drug, however, poses risks for adverse effects when administered systemically. Therefore, we devised a new repurposing strategy in which galunisertib is administered ex vivo. We combined machine perfusion and tissue slices to explore the antifibrotic effects of galunisertib in renal grafts.Experimental ApproachPorcine kidneys were subjected to 30 min of warm ischaemia, 24 h of oxygenated hypothermic machine perfusion and 6 h of normothermic machine perfusion with various treatments (i.e. untreated control, TGFβ1, galunisertib or TGFβ1 + galunisertib; n = 8 kidneys per group). To determine whether effects persisted upon ceasing treatment, kidney slices were prepared from respective kidneys and incubated for 48 h.Key ResultsGalunisertib treatment improved general viability without negatively affecting renal function or elevating levels of injury markers or by‐products of oxidative stress during perfusion. Galunisertib also reduced inflammation and, more importantly, reduced the onset of fibrosis after 48 h of incubation.Conclusions and ImplicationsOur findings demonstrate the value of using machine perfusion for administering antifibrotic drugs such as galunisertib, proving it to be an effective example of repurposing.