Pyruvate-enriched Preservation of Machine Perfused Kidneys

Purpose: Kidney transplantation remains the gold-standard treatment for patients diagnosed with end-stage renal disease (ESRD). However, the demand for donors currently far outpaces the supply. Kidneys donated after cardiac death (DCD) are a promising source, as cardiac arrest remains the leading cause of death in the United States. Studies have demonstrated the efficacy of hypothermic machine perfusion (HMP), a process by which kidneys are cannulated and perfused with a pulsatile flowing solution under hypothermic conditions, in reducing insult to organs compared to standard static cold storage (SCS) [1-3]. To date, perfusate additives to further optimize the outcomes of HMP preserved kidneys have not been extensively studied. The glycolytic end product, pyruvate, has demonstrated efficacy with protecting the heart from ischemia-reperfusion injury, improving post-ischemic contractile function of the heart through its function as an antioxidant and energy substrate, maintaining the glutathione redox state, and inducing erythropoietin production [4, 5]. We aim to investigate the impact of pyruvate on DCD kidneys maintained under HMP conditions. Methods: Cardiovascular death and a period of warm ischemia will be induced in a large animal model, the domestic pig. After explant, one kidney will serve as a pre-perfusion control and the other will be immediately flushed and cannulated to the HMP apparatus. The solutions perfusing the kidney in the HMP machine will consist of either a control perfusate or a pyruvate-enriched perfusate. Sample of the perfusate will be drawn periodically and cytokine concentration will be quantified. Tissue samples from the pre-perfused and 72-hour post-perfusion kidneys will be taken evaluated for both changes in renal tissue integrity via histological assessment and mRNA concentrations of various cytokines. Results: In pyruvate treated DCD kidneys, both renal cortex and renal medulla samples demonstrated better preserved tissue integrity compared to control. Additionally, markers for pro-inflammatory response markedly increased in the control group compared to the treatment group and vice versa for anti-inflammatory markers, including erythropoietin. Conclusions: We expect pyruvate preserved DCD kidneys will experience improved preservation by dampening the rate of increase of pro-inflammatory markers and increasing the concentration of anti-inflammatory markers.