Ischemia–reperfusion (IR) is a complex pathophysiological process encompassing activation of inflammatory responses and cell death programs, the severity of which critically influences both the short and long term outcome of the graft. Given the major organ shortage crises, preserving the function of kidney grafts is of utmost importance, therefore new therapeutic strategies targeting IR injuries – main stumbling block towards enlarged quality organ procurement – are critically needed. As technologies under clinical development focus on minimizing cellular damages after IR injuries had developed by treating the transplant receiver, we think that approaches directed at limiting the injuries directly at the organ level will be highly beneficial, and result in less organ degradation and optimized recovery of function.

Using primary renal proximal tubular endothelial cells, which constitute the most prominent target of IR injury, we developed a new high-throughput phenotypic screening assay that models the transplant process. In order to greatly speed up the discovery time and thus the delivery to the patients' bedside, we chose to screen about 2,000 compounds among well-established pharmaceutical agents. Given the complex pathogenesis of IR and the fact that cellular damages initiated during ischemia are exacerbated during reperfusion, we performed the screening assay in two distinct settings: either the compounds were added prior to the hypoxia, or immediately after the onset of the reoxygenation. This setup allowed us to identify several cytoprotective compounds that we further tested as mixtures to assess potential synergistic effect, and led us to discover BT0113 as a potent combination therapy against the deleterious effects induced by IR injuries.

The fixed-dose combination BT0113 represents a new paradigm in the treatment of renal ischemia-reperfusion injuries that could simply be added to common preservation solutions. Mechanism of action studies for the identified pharmacological modulators of IR are underway, which will help to improve the current knowledge about the molecular and immunological consequences of BT0113 treatment on renal ischemia and reperfusion injuries.

CITATION INFORMATION: Thomas M, Tardif G, Melanger A, Berna P. Modulating Ischemia-Reperfusion Injuries with Pharmacological Agents: A Bench-to-Bedside Approach. Am J Transplant. 2017;17 (suppl 3).

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