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Static cold storage, the mainstay of organ preservation for transplantation at a time when “ideal donors” formed the bulk of the donor pool, has promptly shown its limitations as soon as less-ideal donors, particularly donors after circulatory death, started being used. Hypothermic machine perfusion (HMP) with the recirculation of the perfusion fluid has long been a pathfinder due to its technical simplicity, but soon thereafter, more refinements such as hypothermic oxygenated perfusion and normothermic machine perfusion (NMP) followed. Although the ultimate goal of these technologies was reducing the delayed graft function and improving graft survival, another question was simultaneously explored, namely finding whether various parameters obtained during organ perfusion such as perfusion pressure, perfusate flow and intravascular (renal) resistance can assess the quality of the prospective grafts before transplantation or correlate with outcomes, and ultimately to assist in clinical decision-making on whether to accept an organ for transplantation.1 Whereas renal HMP consistently appears to improve short- and long-term results, its potential as a stand-alone organ quality assessment tool is less reliable.2 Gradually, a third opportunity of perfusion technologies emerged, that is, the possibility for therapeutic interventions during the perfusion session. These hypotheses were tested in several organ types with various degrees of success. NMP involves perfusing an organ with warm, usually blood-based, perfusate at 37 °C to restore circulation and cellular metabolism and to mitigate the cellular and metabolic impairments induced by ischemia. The isolated organ resumes parts of its functions, and various pharmacologic interventions can be initiated. Whereas liver NMP has made tremendous progress during the past decade and is increasingly adopted in clinical use, renal NMP has garnered much less attention (and success). In the case of the liver, lactate and transaminase kinetics in the blood-based perfusate, together with bile production, are sufficient to validate NMP as an organ assessment tool. In contrast, the relative adequacy of HMP alternatives for kidney storage, the limited understanding of metabolic and molecular events during kidney NMP, and the lack of reliable viability biomarkers for kidneys have led to the implementation of renal NMP lagging behind other organs. In this issue of Transplantation, Ogurlu et al3 present a study in which paired porcine kidneys removed either immediately or after 75 min of warm ischemia were submitted to 6 h of hypothermic oxygenated perfusion followed by 6 h of NMP. After NMP, tissue samples were analyzed using metabolomics, transcriptomics, and proteomics. The authors report significant metabolic differences between quasi-pristine kidneys and kidneys with significant ischemic injury that develop during NMP. The study provides and integrates a wealth of new knowledge and signals that numerous metabolic pathways, particularly glycolysis, gluconeogenesis, and the tricarboxylic acid cycle, remain downregulated despite 6 h of uneventful NMP. At the same time, the study revealed the differential upregulation of several pathways related to cellular senescence, increased immune response, and apoptosis. These findings are likely secondary to a combination of reduced activity of several sirtuins and mitochondrial alterations, including the formation of mitochondrial permeability transition pores, which can ultimately lead to NF-kB activation and innate immune activation, in line with previous renal NMP studies from several other groups. Interestingly, but not entirely surprising, oxidized nicotinamide adenine dinucleotide (NAD+) concentrations were found to be significantly decreased in ex vivo kidneys compared with in vivo conditions, even after 6 h of NMP. This suggests an inadequacy of the current strategy of catering for the metabolic needs of an organ, assuming a normal or near-normal energetic and metabolic profile, despite an “adequate” supply of glucose as an energetic substrate. These findings advocate for more abundant supplementation of NAD+ precursors in perfusion fluid, as is already done in several cell culture media. The ex vivo setting would likely allow the use of higher concentrations and other compounds (ie, nicotinamide riboside) as those found in the vitamin cocktail used herein. The study and the results thereof are based on cortical biopsies. However, the renal medulla has a higher oxygen consumption and metabolic demand due to the need to generate and to maintain osmotic gradients and actively reabsorb sodium chloride, an essential process for urine concentration and water reabsorption. In addition, the mitochondria-rich tubular cells of the medullary thick ascending limbs are highly dependent on energy, particularly vulnerable, and the first to be affected by ischemia. Thus, it is possible that the metabolic alterations reported herein are even more pronounced in the medulla. This limitation, partly acknowledged by the authors, may open the way for further studies using selective microdialysis from the cortical and medullary parts of the kidney to complete the current observations. Another limitation of this study is the relatively short perfusion period. Six additional hours of perfusion do not significantly improve the logistics of organ procurement and transplantation. Moreover, interventions aimed at repair and restoration would likely take a longer time to become effective. A recent report indicated that renal NMP is feasible and safe for up to 23 h, a time frame that allows ample time for serial assessments of potential biomarkers and meaningful reconditioning interventions.4 However, as this study design has been used previously by the same group, the current data complete and complement previous observations.5 The assessment at a single end point after 6 h of NMP may also be regarded as another limitation. Thus, it is unclear whether these changes reflected an ongoing worsening or reached a steady state, as previous studies indicated a dynamic hemodynamic and molecular landscape during the first hours of NMP. Therefore, it would be very important to know whether and to what extent the changes reported herein could further evolve if the duration of perfusion is extended. Although resuming organ metabolism at 37 °C by the means of NMP is considered by many a “near-normal” setting or a “surrogate of reperfusion,” this study and several others indicate that this is not entirely the case, as deleterious processes continue or are initiated during NMP. The insights gained from this study could be essential for improving perfusion protocols, optimizing perfusate composition, and refining targeted metabolic and restorative interventions.