Role of blood lactate levels in kidney suitability for donation after circulatory death: a retrospective analysis

This present study aims to investigate the Donation after Circulatory Death (DCD) procedure and the ischemia-reperfusion injury that occurs during organ preservation by examining the correlation between lactate levels during normothermic reperfusion (NrP) and the positive criterion of eligibility and suitability of the organ for DCD transplantation. This retrospective study was approved by the Ethics Committee of our institution. Data were retrieved from DCD kidney donors who were patients admitted to the Intensive Care Unit (ICU) of Ospedale Civile di Baggiovara, Modena (Italy), between 2018 and 2019 and comprised various parameters related to DCD donors, including age, reason for ICU admission, administration of noradrenaline infusion exceeding the dosage of 0.3 mcg/kg/min, duration of ICU stay, lactate levels during normothermic reperfusion (NrP), blood flow during NrP, time of NrP and the criterion of eligibility and suitability of the organ for transplantation as per the Karpinski score. Additionally, when available, short-term information regarding graft complications or organ rejection was also recorded. This manuscript adheres to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. Univariate analysis showed that T0 lactates (odds ratio (OR): 2.20, 95% confidence interval (CI) 1.04–4.71; p = 0.038) and age (OR: 0.69, 95% CI 0.51–0.93; p = 0.016) were significantly associated with the outcome of organ suitability for transplantation. Additionally, lactate levels exhibited a decrease during NrP time, as indicated by a linear mixed model effect, with p-values of 0.004 for the outcome of organ suitability for transplantation and 0.004 for time. Statistical analyses indicate no negative correlation between an increase in lactate levels in the blood during explantation and negative outcomes. Conversely, higher levels of lactate in younger and healthier patients may suggest better mitochondrial function, while a significant decrease in lactate levels may indicate reduced organ damage and increased suitability for transplantation.

Lactate level; Organ suitable; Donation after circulatory death

[1] Manara AR, Murphy PG, O’Callaghan G. Donation after circulatory death. British Journal of Anaesthesia. 2012; 108: i108–i121.

[2] Chazelas P, Steichen C, Favreau F, Trouillas P, Hannaert P, Thuillier R, et al. Oxidative stress evaluation in ischemia reperfusion models: characteristics, limits and perspectives. International Journal of Molecular Sciences. 2021; 22: 2366.

[3] Zhou M, Yu Y, Luo X, Wang J, Lan X, Liu P, et al. Myocardial ischemia-reperfusion injury: therapeutics from a mitochondria-centric perspective. Cardiology. 2021; 146: 781–792.

[4] Nieuwenhuijs-Moeke GJ, Pischke SE, Berger SP, Sanders JSF, Pol RA, Struys MMRF, et al. Ischemia and reperfusion injury in kidney transplantation: relevant mechanisms in injury and repair. Journal of Clinical Medicine. 2020; 9: 253.

[5] Koyama T. Postconditioning with lactate-enriched blood for reducing lethal reperfusion injury in humans. Journal of Cardiovascular Translational Research. 2023; 16: 793–802.

[6] Casiraghi G, Poli D, Landoni G, Buratti L, Imberti R, Plumari V, et al. Intrathecal lactate concentration and spinal cord injury in thoracoabdominal aortic surgery. Journal of Cardiothoracic and Vascular Anesthesia. 2011; 25: 120–126.

[7] Liu GY, Xie WL, Wang YT, Chen L, Xu ZZ, Lv Y, et al. Calpain: the regulatory point of myocardial ischemia-reperfusion injury. Frontiers in Cardiovascular Medicine. 2023; 10: 1194402.

[8] Panconesi R, Carvalho MF, Eden J, Fazi M, Ansari F, Mancina L, et al. Mitochondrial injury during normothermic regional perfusion (NRP) and hypothermic oxygenated perfusion (HOPE) in a rodent model of DCD liver transplantation. EBioMedicine. 2023; 98: 104861.

[9] Callaghan CJ, Charman SC, Muiesan P, Powell JJ, Gimson AE, van der Meulen JH; UK Liver Transplant Audit. Outcomes of transplantation of livers from donation after circulatory death donors in the UK: a cohort study. BMJ Open. 2013; 3: e003287.

[10] Silva A, Arora S, Dhanani S, Rochon A, Giorno LP, Jackson E, et al. Quality improvement tools to manage deceased organ donation processes: a scoping review. BMJ Open. 2023; 13: e070333.

[11] Bissolati M, Cerchione R, Terulla A, Corsini C, Lee YH, Secchi A, et al. Renal resistance trend during hypothermic machine perfusion correlates with preimplantation biopsy score in transplantation of kidneys from extended criteria donors. Transplantation Proceedings. 2021; 53: 1823–1830.

[12] Marletta S, Di Bella C, Catalano G, Mastrosimini MG, Becker J, Ernst A, et al. Pre-implantation kidney biopsies in extended criteria donors: from on call to expert pathologist, from conventional microscope to digital pathology. Critical Reviews in Oncogenesis. 2023; 28: 7–20.

[13] Zagni M, Croci GA, Cannavò A, Passamonti SM, De Feo T, Boggio FL, et al. Histological evaluation of ischemic alterations in donors after cardiac death: a useful tool to predict post-transplant renal function. Clinical Transplantation. 2022; 36: e14622.

[14] Mori G, Cerami C, Facchini F, Fontana F, Alfano G, Giovanni R, et al. Kidney transplantation from circulatory death donors: monocentric experience. Transplantation Proceedings. 2019; 51: 2865–2867.

[15] Ruberto F, Lai Q, Piazzolla M, Brisciani M, Pretagostini R, Garofalo M, et al. The role of hypothermic machine perfusion in selecting renal grafts with advanced histological score. Artificial Organs. 2022; 46: 1771–1782.

[16] Ma H, Guo X, Cui S, Wu Y, Zhang Y, Shen X, et al. Dephosphorylation of AMP-activated protein kinase exacerbates ischemia/reperfusion-induced acute kidney injury via mitochondrial dysfunction. Kidney International. 2022; 101: 315–330.

[17] Lesnefsky EJ, Chen Q, Tandler B, Hoppel CL. Mitochondrial dysfunction and myocardial ischemia-reperfusion: implications for novel therapies. Annual Review of Pharmacology and Toxicology. 2017; 57: 535–565.

[18] Kim M, Stepanova A, Niatsetskaya Z, Sosunov S, Arndt S, Murphy MP, et al. Attenuation of oxidative damage by targeting mitochondrial complex I in neonatal hypoxic-ischemic brain injury. Free Radical Biology & Medicine. 2018; 124: 517–524.

[19] Stepanova A, Kahl A, Konrad C, Ten V, Starkov AS, Galkin A. Reverse electron transfer results in a loss of flavin from mitochondrial complex I: potential mechanism for brain ischemia reperfusion injury. Journal of Cerebral Blood Flow and Metabolism. 2017; 37: 3649–3658.

[20] Chen Q, Hoppel CL, Lesnefsky EJ. Blockade of electron transport before cardiac ischemia with the reversible inhibitor amobarbital protects rat heart mitochondria. The Journal of Pharmacology and Experimental Therapeutics. 2006; 316: 200–207.

[21] Lesnefsky EJ, Tandler B, Ye J, Slabe TJ, Turkaly J, Hoppel CL. Myocardial ischemia decreases oxidative phosphorylation through cytochrome oxidase in subsarcolemmal mitochondria. The American Journal of Physiology. 1997; 273: H1544–H1554.

[22] Quader M, Akande O, Toldo S, Cholyway R, Kang L, Lesnefsky EJ, et al. The commonalities and differences in mitochondrial dysfunction between ex vivo and in vivo myocardial global ischemia rat heart models: implications for donation after circulatory death research. Frontiers in Physiology. 2020; 11: 681.

[23] Schlegel A, Mergental H, Fondevila C, Porte RJ, Friend PJ, Dutkowski P. Machine perfusion of the liver and bioengineering. Journal of Hepatology. 2023; 78: 1181–1198.

[24] Panconesi R, Widmer J, Carvalho MF, Eden J, Dondossola D, Dutkowski P, et al. Mitochondria and ischemia reperfusion injury. Current Opinion in Organ Transplantation. 2022; 27: 434–445.

[25] Schlegel A, Muller X, Mueller M, Stepanova A, Kron P, de Rougemont O, et al. Hypothermic oxygenated perfusion protects from mitochondrial injury before liver transplantation. EBioMedicine. 2020; 60: 103014.

[26] Ferguson BS, Rogatzki MJ, Goodwin ML, Kane DA, Rightmire Z, Gladden LB. Lactate metabolism: historical context, prior misinterpretations, and current understanding. European Journal of Applied Physiology. 2018; 118: 691–728.

[27] Arnold M, Méndez-Carmona N, Wyss RK, Joachimbauer A, Casoni D, Carrel T, et al. Comparison of experimental rat models in donation after circulatory death (DCD): in-situ vs. ex-situ ischemia. Frontiers in Cardiovascular Medicine. 2020; 7: 596883.

[28] Brooks GA. The science and translation of lactate shuttle theory. Cell Metabolism. 2018; 27: 757–785.

[29] Parente A, Flores Carvalho M, Schlegel A. Endothelial cells and mitochondria: two key players in liver transplantation. International Journal of Molecular Sciences. 2023; 24: 10091.

[30] Hunt TK, Aslam RS, Beckert S, Wagner S, Ghani QP, Hussain MZ, et al. Aerobically derived lactate stimulates revascularization and tissue repair via redox mechanisms. Antioxidants & Redox Signaling. 2007; 9: 1115–1124.

[31] Nalbandian M, Takeda M. Lactate as a signaling molecule that regulates exercise-induced adaptations. Biology. 2016; 5: 38.

[32] Arnold M, Segiser A, Graf S, Méndez-Carmona N, Sanz MN, Wyss RK, et al. Pre-ischemic lactate levels affect post-ischemic recovery in an isolated rat heart model of donation after circulatory death (DCD). Frontiers in Cardiovascular Medicine. 2021; 8: 669205.

[33] Takahashi K, Jafri SR, Safwan M, Abouljoud MS, Nagai S. Peri-transplant lactate levels and delayed lactate clearance as predictive factors for poor outcomes after liver transplantation: a propensity score-matched study. Clinical Transplantation. 2019; 33: e13613.

[34] Baroni S, Melegari G, Brugioni L, Gualdi E, Barbieri A, Bertellini E. First experiences of hemoadsorption in donation after circulatory death. Clinical Transplantation. 2020; 34: e13874.

[35] Saemann L, Hoorn F, Georgevici AI, Pohl S, Korkmaz-Icöz S, Veres G, et al. Cytokine adsorber use during DCD heart perfusion counteracts coronary microvascular dysfunction. Antioxidants. 2022; 11: 2280.

[36] Baroni S, Marudi A, Rinaldi S, Ghedini S, Magistri P, Piero Guerrini G, et al. Cytokine mass balance levels in donation after circulatory death donors using hemoadsorption: case series report. The International Journal of Artificial Organs. 2022; 45: 642–646.

[37] Niederberger P, Farine E, Arnold M, Wyss RK, Sanz MN, Méndez-Carmona N, et al. High pre-ischemic fatty acid levels decrease cardiac recovery in an isolated rat heart model of donation after circulatory death. Metabolism. 2017; 71: 107–117.

[38] Kadowaki S, Siraj MA, Chen W, Wang J, Parker M, Nagy A, et al. Cardioprotective actions of a glucagon-like peptide-1 receptor agonist on hearts donated after circulatory death. Journal of the American Heart Association. 2023; 12: e027163.

[39] Quader M, Mezzaroma E, Kenning K, Toldo S. Modulation of interleukin-1 and -18 mediated injury in donation after circulatory death mouse hearts. The Journal of Surgical Research. 2021; 257: 468–476.

[40] Quader M, Chen Q, Akande O, Cholyway R, Mezzaroma E, Lesnefsky EJ, et al. Electron transport chain inhibition to decrease injury in transplanted donation after circulatory death rat hearts. Journal of Cardiovascular Pharmacology. 2023; 81: 389–391.

[41] Aceros H, Der Sarkissian S, Borie M, Pinto Ribeiro RV, Maltais S, Stevens LM, et al. Novel heat shock protein 90 inhibitor improves cardiac recovery in a rodent model of donation after circulatory death. The Journal of Thoracic and Cardiovascular Surgery. 2022; 163: e187–e197.