*Purpose: The use of marginal has increased due to ongoing donor shortages. These kidneys have higher rates of graft discard after procurement, and also have inferior post-transplantation outcomes compared to standard brain-dead donor kidneys when the current gold standard cold static storage (CS) is used as the preservation modality. We aimed to investigate the utility of normothermic machine perfusion (NMP) as a viable alternate and superior preservation strategy using a series of discarded human kidneys. Specific aims were to: (i) investigate NMP feasibility and functional outcomes in human kidneys, and (ii) compare NMP to CS alone using discarded human kidney pairs in a simulated transplantation setting.

*Methods: Deceased donor kidneys were obtained if deemed unsuitable for transplantation . (A) Single kidneys underwent NMP after a period of CS during transportation at a mean arterial pressure of 75-85 mmHg and temperature 37⁰C. System feasibility and perfusion success was judged by the quality of perfusion, perfusion parameters (renal blood flow [RBF] and intra-renal resistance [IRR]), urine output [UO], and renal functional parameters (oxygen consumption, tubular function [FeNa], creatinine clearance [CrCl]). (B) For single kidneys discarded due to poor in situ perfusion at retrieval, NMP was utilized to improve the non-perfused region. (C) If a pair of kidneys was obtained from a single donor, one kidney was maintained in CS, and the other underwent 1 hour of NMP after CS. This was followed by ex vivo reperfusion using whole allogeneic blood in both kidneys. In addition to perfusion and functional parameters, whole transcriptome gene sequencing and indicators of ischemia-reperfusion injury (IRI) were compared.

*Results: Fifteen kidneys were obtained. (A) All kidneys were successfully perfused using our NMP device. Fourteen of 15 kidneys produced urine, and all kidneys demonstrated evidence of creatinine clearance (CrCl) and renal tubular function. Autologous donor packed red blood cells were isolated in 4 cases, and were able to achieve similar perfusion parameters, CrCl (p = 0.581) and FeNa (p = 0.900) during NMP as compared to banked blood. Donor-specific leukocyte efflux from the grafts was assessed using flow cytometry, with evidence of extravasation of granulocytes, B and T cells, and NK cells. (B) Kidneys that were discarded due to poor perfusion at retrieval were successfully perfused, with complete resolution of the poorly perfused region(s). (C) Eight kidneys (i.e. 4 pairs) were used to directly compare NMP and CS. During simulated transplantation, NMP kidneys had significantly better flows and resistance (p < 0.05), FeNa (p = 0.034), and trends to better CrCl and oxygen consumption (p = 0.062). Immunofluorescence techniques showed evidence of reduced injury, with a reduction in cell death, complement activation, and oxidative stress in NMP kidneys (p < 0.05). Whole transcriptome gene sequencing demonstrated the differential expression of 495 genes between the NMP and CS paired kidneys, including pathways involved in immunity/inflammation, oxidative stress, and cell death.

*Conclusions: NMP is superior to CS in the immediate post-transplant period, allowing for the rejuventation of marginal kidneys. NMP also has strong potential to reduce organ discards.

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