Metabolic needs of the kidney graft undergoing normothermic machine perfusion

Normothermic machine perfusion (NMP) is emerging as a novel preservation strategy. During NMP, the organ maintained in metabolically active state that may not only provide superior preservation, but also facilitates viability testing before transplantation, and ex situ resuscitation of marginal kidney grafts. Although prevailing protocols for renal NMP are refined from initial pioneering studies concerning short periods it could be argued these optimally tailored to address putatively compromised metabolic plasticity donor grafts (i.e., context and/or preservation), or meet prerequisites associated with prolonged perfusions required anabolic regeneration. Herein, we theoretical framework requirements NMP. Aspects discussed along lines carbohydrates, fatty acids, amino micronutrients optimal an isolated kidney. In addition, considerations monitoring aspects status during discussed. The key challenge transplantation global shortage organs. Because pressing demands, most transplant centers progressively embracing organs older higher-risk donors. At same time, many discarded because perceived risk function, function suboptimally after transplantation.1De Meester J. expanded criteria transplant: nearly new car.Transplant Int. 2017; 30: 11-13Crossref PubMed Scopus (1) Google Scholar One strategy increase graft utility improve outcomes implementation more objective quality assessment tools by organs, thereby creating window functional enhancement perfused graft, 4Rs: resuscitation,2Nicholson M.L. Hosgood S.A. Renal vivo normothermic perfusion: first clinical study.Am J Transplant. 2013; 13: 1246-1252Crossref (198) repair,3Rijkse E. de Jonge Kimenai H.J.A.N. et al.Safety feasibility 2 h kidneys Eurotransplant Senior Program.BJS Open. 2021; 5: zraa024Crossref (5) rejuvenation,4Hameed A.M. Lu D.B. Patrick al.Brief rejuvenates human kidneys.Transplant Direct. 2019; 5e502Crossref regeneration.5Weissenbacher A. Lo Faro L. Boubriak O. al.Twenty-four-hour urine recirculation.Am 19: 178-192Crossref (35) Multiple trials have shown hypothermic feasible safe, improves outcomes.6Tingle S.J. Figueiredo R.S. Moir J.A.G. al.Machine versus static cold storage deceased transplantation.Cochrane Database Syst Rev. 3: CD011671PubMed Scholar, 7Moers C. Smits J.M. Maathuis M.H. deceased-donor transplantation.N Engl Med. 2009; 360: 7-19Crossref (697) 8Rijkse Ijzermans J.N. Minnee R.C. Machine abdominal transplantation: current use Netherlands.World 2020; 10: 15-28Crossref An obvious next step was introduction (sub)normothermic (NMP).9Hosgood Nicholson First man perfusion.Transplantation. 2011; 92: 735-738Crossref (118) has been proved several trials,10Minor T. von Horn Gallinat al.First-in-man controlled rewarming cell-free solution prior transplantation.Am 20: 1192-1195Crossref (13) Scholar,11Hosgood Saeb-Parsy K. Wilson al.Protocol randomised controlled, open-label trial donation circulatory death transplantation.BMJ 7e012237Crossref (75) reflect proof-of-concept studies, primarily concerned specific may, some extent, vary aims perfusion; 4 Rs. Shorter at resuscitation, rejuvenation, should metabolites sustain flexibility. Longer aim repair rejuvenation come additional need factors, such essential acids vitamins. Current all based on continuous red blood cells alternate oxygen carrier, isotonic or/and colloid solution, albumin, glucose acids2Nicholson 3Rijkse 4Hameed 5Weissenbacher Scholar,10Minor 11Hosgood 12Aburawi M.M. Fontan F.M. Karimian N. al.Synthetic hemoglobin-based carriers acceptable alternative packed perfusion.Am 2814-2824Crossref (14) 13Kabagambe S.K. Palma I.P. Smolin Y. al.Combined high-risk transplantation.Transplantation. 103: 392-400Crossref (9) energy source.14Elliott T.R. overview strategies.Am 21: 1382-1390Crossref (10) A detailed published (including perfusate composition) provided Table 1.2Nicholson Scholar,3Rijkse Scholar,9Hosgood ScholarTable 1Overview hardware (perfusion control mode, pressure, gas supply), composition, supplements different protocols2Nicholson ScholarPerfusate compositionsHosgood al. (2013, 2017)Weissenbacher (2018)Kabagambe (2018)Aburawi (2019)Hameed (2019)Minor (2020)Rijkse (2021)Arykbaeva (NCT04693325)Perfusion mode MachineBio-Console 560Prototype OrganOxBio-Console 560Kidney Assist (Organ Assist)Cardiopulmonary bypass technologyKidney Assist)Kidney Assist) PumpCentrifugalCentrifugalCentrifugalCentrifugalRollerCentrifugalCentrifugalCentrifugal Temperature37 °C37 °CFrom 8 °C 35 (within 90 min)37 PressureFlow up 75 mm HgFlow between 70–100 Hg70–80 Hg70 Hg75–85 HgFrom 30 Hg min)Increased 60 Hg, if necessary 100 HgPressure Oxygenation95% O2/5% CO2 0.1 L/minProportional valves; 10 ml/min; pO2 10–26 kPa pCO2 2–6 kPa95% CO295% 1.5 L/minpO2 values >500 Hg100% O295% 0.5 L/min SystemClosedClosedClosedOpenOpenOpenOpenOpen Duration h124361–31.526Baseline additives start (per liter) Total volume, L?0.6–0.70.50.520.7520.75–1.251 Oxygen carrierRBCRBCRBCRBC HBOCRBCSTEEN solutionRBCRBC430–500 ml/L500 ml/L250 ml/L334 ml/L188–313 ml/L Isotonic solutionRinger's solutionNonePlasma-Lyte AWilliams E MediaRinger's solutionSterofundin solutionSodium chloride500–570 ml/L750 ml/L200 ml/L667–1250 ml/LSterile water33.4 Colloid—HSA——Gelofusine——HSA500 ml 5%/L333 40%/L100 20%/L Other additivesSodium bicarbonate 8.4%Sodium 8.4%titrated pH 7.3–7.410.0–30.0 mmol/L52.4 mmol/Ltitrated 7.3–7.420.0 mmol/L11.0 mmol/L10.3–420.0 mmol/L20.0–30.0 mmol/L—Calcium gluconate 10%—Calcium 10%Calcium 10%4.4 1.1–1.4 mmol/L1.5 mmol/L0.8 mmol/L4.4 mmol/LMannitol 10%Mannitol 10%——Mannitol 10%—Mannitol 10%19.9–23.2 mmol/L11.1 mmol/L—36.7 mmol/L4.17–13.9 mmol/L—Cefuroxime——AmpicillinAugementinCefazolin1.5 g/L0.5 g/L9–15 g/L2 g/LHeparinHeparinHeparinHeparin—Heparin—2865–3334 IU/L—4000 IU/L1000 IU/L2670 IU/L1500–5000 IU/LDexamethasone——Dexamethasone——Dexamethasone—11.4–13.3 mg/L8 mg/L6–8 mg/LContinuous (calculated per hour) Metabolic substrateAmino (total)Synthamin 17 1.89 g/h 3.44 mmol/L sodium bicarbonateNutriflex (only acids) 0.14 gaWhen <4 mmol/L.Clinimex 2.75/10 0.55 g/hWilliams Media 0.305 g/hM199 0.014 g/h—Nutriflex 1.15 bicarbonateAminoplasmal 10% 2.33 g/hof which glutamine0 g/h0.0123 mmol/L.None0.019 g/h0.0013 g/h—0.01 g/h1.68 g/hGlucose1.39–1.94 mmol/h0.003 mmolaWhen mmol/L.11.1 mmol/h (dextrose)Titrated 5.5–11.1 (dextrose) 4.16 (in Williams Media)1.39 (dextrose 5%) 0.11 M199)—1.94 mmol/h2.22 mmol/hInsulin, IU/h3.78—25——3.78—MultivitaminsCernevit—Infutive Adult(in Media)(in M199)—MultivitaminsCernevit5 Urine replacementRinger’s solutionRecirculationPlasma-Lyte ARinger’s lactateRinger’s solution—RecirculationRecirculation VasodilatorProstacyclinProstacyclin——Verapamil—ProstacyclinProstacyclin0.05 mg/h0.004 mg/h12.5 mg/h0.05 mg/h0.009 mg/hHBOC, hemoglobulin-based carrier; pCO2, partial pressure carbon dioxide; pO2, oxygen; RBC, cell.With exception, successful transplantations al.2Nicholson (following 1-hour NMP), Minor al.10Minor hours rewarming), Rijkse al.3Rijkse none transplanted. 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