Ischemia/reperfusion-associated tubular cells injury in renal transplantation: Can metabolomics inform about mechanisms and help identify new therapeutic targets?

Tubular cells are central targets of ischemia-reperfusion (I/R) injury in kidney transplantation. Inflammation and metabolic disturbances occurring within these cells are deleterious by themselves but also favor secondary events, such as activation of immune response. It is critical to have an in depth understanding of the mechanisms governing tubular cells response to I/R if one wants to define pertinent biomarkers or to elaborate targeted therapeutic interventions. As oxidative damage was shown to be central in the patho-physiological mechanisms, the impact of I/R on proximal tubular cells metabolism has been widely studied, contrary to its effects on expression and activity of membrane transporters of the proximal tubular cells. Yet, temporal modulation of transporters over ischemia and reperfusion periods appears to play a central role, not only in the induction of cells injury but also in graft function recovery. Metabolomics in cell models or diverse biofluids has the potential to provide large pictures of biochemical consequences of I/R. Metabolomic studies conducted in experimental models of I/R or in transplanted patients indeed retrieved metabolites belonging to the pathways known to be particularly affected. Interestingly, they also revealed that metabolic disturbances and transporters activities are in very close mutual interplay. As well as helping to select diagnostic biomarkers, such analyses could also contribute to identify new pharmacological targets and to set up innovative nephroprotective strategies for the future. Even if various therapeutic approaches have been evaluated for a long time to prevent or treat I/R injuries, metabolomics has helped identifying new ones, those related to membrane transporters seeming to be of particular interest. However, considering the very complex and multifactorial effects of I/R in the context of kidney transplantation, all tracks must be followed if one wants to prevent or limit its deleterious consequences.