Effects of warm ischaemia combined with cold preservation on the hypoxia-inducible factor 1α pathway in an experimental renal autotransplantation model

International audienceBackgroundThe increased use of marginal donors highlights the importance of organ quality in transplantation and the identification of prognostic biomarkers. This experimental study investigated modulation of the hypoxia-inducible factor (HIF) 1 pathway in kidney grafts in relation to different degrees of ischaemia. MethodsIn a porcine autotransplantation model, two different kidney graft protocols were compared: standard 24-h cold storage (CS) and 24-h CS preceded by 1h warm ischaemia (WI+CS). The renal HIF-1 pathway and tubular dedifferentiation were analysed in the early phase of reperfusion and at 3months. ResultsThere was a relationship between the degree of ischaemic injury and the outcome of the kidney graft. During the first week of reperfusion, WI+CS grafts showed a higher degree of injury. The observed tubular dedifferentiation was associated with delayed HIF-1 expression, and with loss of its role in transcription. In highly injured kidneys, deregulation of the HIF-1 pathway was also observed in the chronic phase, with reduced production of vascular endothelial growth factor (VEGF) A, and upregulation of VEGF receptor 1 (Flt-1) and thrombospondin 1. In addition, these kidneys displayed altered kidney histology and decreased function. ConclusionThe HIF-1 pathway appears to be abolished early in response to severe ischaemia. A high degree of ischaemic injury also results in chronic activation of the HIF-1 pathway, diverting it away from the beneficial activation of angiogenesis. Further studies on the finely tuned balance of signals in this pathway may provide diagnostic biomarkers that can determine organ quality during kidney transplantation