Metabolic needs of the kidney graft undergoing normothermic machine perfusion

Abstract

Normothermic machine perfusion (NMP) is emerging as a novel preservation strategy. During NMP, the organ is maintained in a metabolically active state that may not only provide superior organ preservation, but that also facilitates viability testing before transplantation, and ex situ resuscitation of marginal kidney grafts. Although the prevailing perfusion protocols for renal NMP are refined from initial pioneering studies concerning short periods of NMP, it could be argued that these protocols are not optimally tailored to address the putatively compromised metabolic plasticity of marginal donor grafts (i.e., in the context of viability testing and/or preservation), or to meet the metabolic prerequisites associated with prolonged perfusions and the required anabolic state in the context of organ regeneration. Herein, we provide a theoretical framework for the metabolic requirements for renal NMP. Aspects are discussed along the lines of carbohydrates, fatty acids, amino acids, and micronutrients required for optimal NMP of an isolated kidney. In addition, considerations for monitoring aspects of metabolic status during NMP are discussed. Normothermic machine perfusion (NMP) is emerging as a novel preservation strategy. During NMP, the organ is maintained in a metabolically active state that may not only provide superior organ preservation, but that also facilitates viability testing before transplantation, and ex situ resuscitation of marginal kidney grafts. Although the prevailing perfusion protocols for renal NMP are refined from initial pioneering studies concerning short periods of NMP, it could be argued that these protocols are not optimally tailored to address the putatively compromised metabolic plasticity of marginal donor grafts (i.e., in the context of viability testing and/or preservation), or to meet the metabolic prerequisites associated with prolonged perfusions and the required anabolic state in the context of organ regeneration. Herein, we provide a theoretical framework for the metabolic requirements for renal NMP. Aspects are discussed along the lines of carbohydrates, fatty acids, amino acids, and micronutrients required for optimal NMP of an isolated kidney. In addition, considerations for monitoring aspects of metabolic status during NMP are discussed. The key challenge in organ transplantation is the global shortage of donor organs. Because of the pressing demands, most transplant centers are progressively embracing organs from older and higher-risk donors. At the same time, many grafts are discarded because of a perceived risk that these organs may not function, or function suboptimally after transplantation.1De Meester J. The expanded criteria donor for kidney transplant: not a nearly new car.Transplant Int. 2017; 30: 11-13Crossref PubMed Scopus (1) Google Scholar One strategy to increase graft utility and improve transplant outcomes is the implementation of more objective quality assessment tools by ex situ perfusion of donor organs, thereby creating a window for functional testing and viability enhancement of the perfused graft, the 4Rs: resuscitation,2Nicholson M.L. Hosgood S.A. Renal transplantation after ex vivo normothermic perfusion: the first clinical study.Am J Transplant. 2013; 13: 1246-1252Crossref PubMed Scopus (198) Google Scholar repair,3Rijkse E. de Jonge J. Kimenai H.J.A.N. et al.Safety and feasibility of 2 h of normothermic machine perfusion of donor kidneys in the Eurotransplant Senior Program.BJS Open. 2021; 5: zraa024Crossref PubMed Scopus (5) Google Scholar rejuvenation,4Hameed A.M. Lu D.B. Patrick E. et al.Brief normothermic machine perfusion rejuvenates discarded human kidneys.Transplant Direct. 2019; 5e502Crossref PubMed Google Scholar and regeneration.5Weissenbacher A. Lo Faro L. Boubriak O. et al.Twenty-four-hour normothermic perfusion of discarded human kidneys with urine recirculation.Am J Transplant. 2019; 19: 178-192Crossref PubMed Scopus (35) Google Scholar Multiple trials have shown that ex situ hypothermic machine perfusion for kidney grafts is feasible and safe, and improves clinical outcomes.6Tingle S.J. Figueiredo R.S. Moir J.A.G. et al.Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation.Cochrane Database Syst Rev. 2019; 3: CD011671PubMed Google Scholar, 7Moers C. Smits J.M. Maathuis M.H. et al.Machine perfusion or cold storage in deceased-donor kidney transplantation.N Engl J Med. 2009; 360: 7-19Crossref PubMed Scopus (697) Google Scholar, 8Rijkse E. Ijzermans J.N. Minnee R.C. Machine perfusion in abdominal organ transplantation: current use in the Netherlands.World J Transplant. 2020; 10: 15-28Crossref PubMed Google Scholar An obvious next step was the introduction of (sub)normothermic machine perfusion (NMP).9Hosgood S.A. Nicholson M.L. First in man renal transplantation after ex vivo normothermic perfusion.Transplantation. 2011; 92: 735-738Crossref PubMed Scopus (118) Google Scholar Although the feasibility of NMP has been proved in several trials,10Minor T. von Horn C. Gallinat A. et al.First-in-man controlled rewarming and normothermic perfusion with cell-free solution of a kidney prior to transplantation.Am J Transplant. 2020; 20: 1192-1195Crossref PubMed Scopus (13) Google Scholar,11Hosgood S.A. Saeb-Parsy K. Wilson C. et al.Protocol of a randomised controlled, open-label trial of ex vivo normothermic perfusion versus static cold storage in donation after circulatory death renal transplantation.BMJ Open. 2017; 7e012237Crossref PubMed Scopus (75) Google Scholar current kidney NMP protocols reflect pioneering proof-of-concept studies, studies that primarily concerned short periods of NMP. The specific metabolic prerequisites may, to some extent, vary with the specific aims of the perfusion; the 4 Rs. Shorter perfusion that aims at resuscitation, rejuvenation, and functional assessment should provide the metabolites that optimally sustain metabolic flexibility. Longer perfusions that aim at repair and rejuvenation come with the additional need for anabolic factors, such as essential amino acids and vitamins. Current protocols are all based on continuous perfusion with red blood cells or an alternate oxygen carrier, an isotonic or/and colloid solution, such as albumin, and glucose and amino acids2Nicholson M.L. Hosgood S.A. Renal transplantation after ex vivo normothermic perfusion: the first clinical study.Am J Transplant. 2013; 13: 1246-1252Crossref PubMed Scopus (198) Google Scholar, 3Rijkse E. de Jonge J. Kimenai H.J.A.N. et al.Safety and feasibility of 2 h of normothermic machine perfusion of donor kidneys in the Eurotransplant Senior Program.BJS Open. 2021; 5: zraa024Crossref PubMed Scopus (5) Google Scholar, 4Hameed A.M. Lu D.B. Patrick E. et al.Brief normothermic machine perfusion rejuvenates discarded human kidneys.Transplant Direct. 2019; 5e502Crossref PubMed Google Scholar, 5Weissenbacher A. Lo Faro L. Boubriak O. et al.Twenty-four-hour normothermic perfusion of discarded human kidneys with urine recirculation.Am J Transplant. 2019; 19: 178-192Crossref PubMed Scopus (35) Google Scholar,10Minor T. von Horn C. Gallinat A. et al.First-in-man controlled rewarming and normothermic perfusion with cell-free solution of a kidney prior to transplantation.Am J Transplant. 2020; 20: 1192-1195Crossref PubMed Scopus (13) Google Scholar, 11Hosgood S.A. Saeb-Parsy K. Wilson C. et al.Protocol of a randomised controlled, open-label trial of ex vivo normothermic perfusion versus static cold storage in donation after circulatory death renal transplantation.BMJ Open. 2017; 7e012237Crossref PubMed Scopus (75) Google Scholar, 12Aburawi M.M. Fontan F.M. Karimian N. et al.Synthetic hemoglobin-based oxygen carriers are an acceptable alternative for packed red blood cells in normothermic kidney perfusion.Am J Transplant. 2019; 19: 2814-2824Crossref PubMed Scopus (14) Google Scholar, 13Kabagambe S.K. Palma I.P. Smolin Y. et al.Combined ex vivo hypothermic and normothermic perfusion for assessment of high-risk deceased donor human kidneys for transplantation.Transplantation. 2019; 103: PubMed Scopus Google Scholar as Nicholson M.L. Hosgood S.A. Normothermic kidney perfusion: an of protocols and J Transplant. 2021; PubMed Scopus Google Scholar of the protocols the is in M.L. Hosgood S.A. Renal transplantation after ex vivo normothermic perfusion: the first clinical study.Am J Transplant. 2013; 13: 1246-1252Crossref PubMed Scopus (198) Google E. de Jonge J. Kimenai H.J.A.N. et al.Safety and feasibility of 2 h of normothermic machine perfusion of donor kidneys in the Eurotransplant Senior Program.BJS Open. 2021; 5: zraa024Crossref PubMed Scopus (5) Google S.A. Nicholson M.L. First in man renal transplantation after ex vivo normothermic perfusion.Transplantation. 2011; 92: 735-738Crossref PubMed Scopus (118) Google Scholar,10Minor T. von Horn C. Gallinat A. et al.First-in-man controlled rewarming and normothermic perfusion with cell-free solution of a kidney prior to transplantation.Am J Transplant. 2020; 20: 1192-1195Crossref PubMed Scopus (13) Google of the and the and during NMP of the kidney for the M.L. Hosgood S.A. Renal transplantation after ex vivo normothermic perfusion: the first clinical study.Am J Transplant. 2013; 13: 1246-1252Crossref PubMed Scopus (198) Google Scholar, 3Rijkse E. de Jonge J. Kimenai H.J.A.N. et al.Safety and feasibility of 2 h of normothermic machine perfusion of donor kidneys in the Eurotransplant Senior Program.BJS Open. 2021; 5: zraa024Crossref PubMed Scopus (5) Google Scholar, 4Hameed A.M. Lu D.B. Patrick E. et al.Brief normothermic machine perfusion rejuvenates discarded human kidneys.Transplant Direct. 2019; 5e502Crossref PubMed Google Scholar, 5Weissenbacher A. Lo Faro L. Boubriak O. et al.Twenty-four-hour normothermic perfusion of discarded human kidneys with urine recirculation.Am J Transplant. 2019; 19: 178-192Crossref PubMed Scopus (35) Google Scholar,10Minor T. von Horn C. Gallinat A. et al.First-in-man controlled rewarming and normothermic perfusion with cell-free solution of a kidney prior to transplantation.Am J Transplant. 2020; 20: 1192-1195Crossref PubMed Scopus (13) Google Scholar, 11Hosgood S.A. Saeb-Parsy K. Wilson C. et al.Protocol of a randomised controlled, open-label trial of ex vivo normothermic perfusion versus static cold storage in donation after circulatory death renal transplantation.BMJ Open. 2017; 7e012237Crossref PubMed Scopus (75) Google Scholar, 12Aburawi M.M. Fontan F.M. Karimian N. et al.Synthetic hemoglobin-based oxygen carriers are an acceptable alternative for packed red blood cells in normothermic kidney perfusion.Am J Transplant. 2019; 19: 2814-2824Crossref PubMed Scopus (14) Google Scholar, 13Kabagambe S.K. Palma I.P. Smolin Y. et al.Combined ex vivo hypothermic and normothermic perfusion for assessment of high-risk deceased donor human kidneys for transplantation.Transplantation. 2019; 103: PubMed Scopus Google et et et et et et et et during NMP to controlled to controlled, to from to controlled at at and at at of NMP, before NMP or of of of to of to of to during NMP acids with amino glucose with glucose glucose to oxygen NMP, normothermic machine perfusion; of of red blood the in the studies of Hosgood et M.L. Hosgood S.A. Renal transplantation after ex vivo normothermic perfusion: the first clinical study.Am J Transplant. 2013; 13: 1246-1252Crossref PubMed Scopus (198) Google S.A. Nicholson M.L. First in man renal transplantation after ex vivo normothermic perfusion.Transplantation. 2011; 92: 735-738Crossref PubMed Scopus (118) Google Scholar et T. von Horn C. Gallinat A. et al.First-in-man controlled rewarming and normothermic perfusion with cell-free solution of a kidney prior to transplantation.Am J Transplant. 2020; 20: 1192-1195Crossref PubMed Scopus (13) Google Scholar 2 continuous and et E. de Jonge J. Kimenai H.J.A.N. et al.Safety and feasibility of 2 h of normothermic machine perfusion of donor kidneys in the Eurotransplant Senior Program.BJS Open. 2021; 5: zraa024Crossref PubMed Scopus (5) Google Scholar 2 of the perfused kidney grafts have been for a of glucose in a new oxygen NMP, normothermic machine perfusion; of of red blood the in the studies of Hosgood et M.L. Hosgood S.A. Renal transplantation after ex vivo normothermic perfusion: the first clinical study.Am J Transplant. 2013; 13: 1246-1252Crossref PubMed Scopus (198) Google S.A. Nicholson M.L. First in man renal transplantation after ex vivo normothermic perfusion.Transplantation. 2011; 92: 735-738Crossref PubMed Scopus (118) Google Scholar et T. von Horn C. Gallinat A. et al.First-in-man controlled rewarming and normothermic perfusion with cell-free solution of a kidney prior to transplantation.Am J Transplant. 2020; 20: 1192-1195Crossref PubMed Scopus (13) Google Scholar 2 continuous and et E. de Jonge J. Kimenai H.J.A.N. et al.Safety and feasibility of 2 h of normothermic machine perfusion of donor kidneys in the Eurotransplant Senior Program.BJS Open. 2021; 5: zraa024Crossref PubMed Scopus (5) Google Scholar 2 of the perfused kidney grafts have been for a of on the that all NMP studies of human kidneys E. de Jonge J. Kimenai H.J.A.N. et al.Safety and feasibility of 2 h of normothermic machine perfusion of donor kidneys in the Eurotransplant Senior Program.BJS Open. 2021; 5: zraa024Crossref PubMed Scopus (5) Google Scholar, 4Hameed A.M. Lu D.B. Patrick E. et al.Brief normothermic machine perfusion rejuvenates discarded human kidneys.Transplant Direct. 2019; 5e502Crossref PubMed Google Scholar, 5Weissenbacher A. Lo Faro L. Boubriak O. et al.Twenty-four-hour normothermic perfusion of discarded human kidneys with urine recirculation.Am J Transplant. 2019; 19: 178-192Crossref PubMed Scopus (35) Google M.M. Fontan F.M. Karimian N. et al.Synthetic hemoglobin-based oxygen carriers are an acceptable alternative for packed red blood cells in normothermic kidney perfusion.Am J Transplant. 2019; 19: 2814-2824Crossref PubMed Scopus (14) Google S.K. Palma I.P. Smolin Y. et al.Combined ex vivo hypothermic and normothermic perfusion for assessment of high-risk deceased donor human kidneys for transplantation.Transplantation. 2019; 103: PubMed Scopus Google Scholar it could be argued that a metabolic state is not the current NMP A. et glucose during kidney is associated with 2020; PubMed Scopus Google et of an clinical and metabolic kidney Int. 2020; PubMed Scopus Google Scholar Although may reflect use of discarded is also during NMP of kidneys that for E. de Jonge J. Kimenai H.J.A.N. et al.Safety and feasibility of 2 h of normothermic machine perfusion of donor kidneys in the Eurotransplant Senior Program.BJS Open. 2021; 5: zraa024Crossref PubMed Scopus (5) Google Scholar current NMP perfusion protocols not the optimal required for of a metabolic state in that the protocols the optimal for viability testing or prolonged perfusions required for resuscitation and/or repair of kidney grafts. The kidney is a metabolically active with a that is to the A. et metabolic of organs and by of J 92: PubMed Scopus Google Scholar and has specific and metabolic The aspects are by the of and shown by C. et organs in 2019; 30: Scopus Google Scholar and by in A. et glucose during kidney is associated with 2020; PubMed Scopus Google J. 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