*Purpose: Prolonged cold ischemia is a known risk factor for delayed graft function and poorer outcomes after kidney transplantation. Overcoming this obstacle is key to increasing the availability of organs for transplantation. The role of donor kidney resident macrophages in potentiating early ischemic injury remains to be explored.

*Methods: Utilizing a syngeneic kidney transplantation model, grafts from C57BL/6J mice were harvested and stored in cold UW solution for 3.5 hours followed by transplantation into age-matched, bilaterally-nephrectomized C57BL/6J recipients. Prior to transplant, donor mice were either treated with macrophage depleting agent, liposomal clodronate (LC), or left untreated. Macrophage-depletion in the kidney was achieved by daily intravenous LC for 7 days, initiated 14 days prior to transplant.

*Results: Macrophage depletion of the donor kidney resulted in significantly better kidney function after transplantation, when compared to non-depleted kidney graft recipients. After 48 hours, mean creatinine value in the macrophage depletion group was 2.1 mg/dl lower than that of their untreated counterparts. A similar trend in blood urea nitrogen values was seen however it was not statistically significant. Furthermore, short term survival of mice that received macrophage depleted syngeneic grafts was significantly better as well. Ischemic injury leads to release of damage/danger associated molecular patterns (DAMPs) which activates pattern recognition receptor (PRRs) on macrophages resulting in a proinflammatory response. These macrophages further lead to maladaptive repair. Since kidney resident macrophages are the first responders to this insult, we have shown that their absence is protective.

*Conclusions: Donor macrophage depletion prior to transplantation is protective despite prolonged cold ischemia. This provides a unique opportunity to increase the utility of organs subjected to long cold ischemic durations. Furthermore, we feel donor macrophage depletion has wide applicability as this therapy has the future potential to be delivered during ex-vivo perfusion of the donor kidney.

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