TY - JOUR
T1 - Normothermic Machine Perfusion Reconstitutes Porcine Kidney Tissue Metabolism But Induces an Inflammatory Response, Which Is Reduced by Complement C5 Inhibition
AU - de Boer, Eline
AU - Sokolova, Marina
AU - Jager, Neeltina M.
AU - Schjalm, Camilla
AU - Weiss, Marc G.
AU - Liavåg, Olav M.
AU - Maassen, Hanno
AU - van Goor, Harry
AU - Thorgersen, Ebbe Billmann
AU - Pettersen, Kristin
AU - Christiansen, Dorte
AU - Ludviksen, Judith Krey
AU - Jespersen, Bente
AU - Mollnes, Tom E.
AU - Leuvenink, Henri G.D.
AU - Pischke, Søren E.
N1 - Publisher Copyright:
Copyright © 2024 de Boer, Sokolova, Jager, Schjalm, Weiss, Liavåg, Maassen, van Goor, Thorgersen, Pettersen, Christiansen, Ludviksen, Jespersen, Mollnes, Leuvenink and Pischke.
PY - 2024/11/13
Y1 - 2024/11/13
N2 - Normothermic machine perfusion (NMP) is a clinical strategy to reduce renal ischemia-reperfusion injury (IRI). Optimal NMP should restore metabolism and minimize IRI induced inflammatory responses. Microdialysis was used to evaluate renal metabolism. This study aimed to assess the effect of complement inhibition on NMP induced inflammatory responses. Twenty-two pig kidneys underwent 18 h of static cold storage (SCS) followed by 4 h of NMP using a closed-circuit system. Kidneys were randomized to receive a C5-inhibitor or placebo during SCS and NMP. Perfusion resulted in rapidly stabilized renal flow, low renal resistance, and urine production. During SCS, tissue microdialysate levels of glucose and pyruvate decreased significantly, whereas glycerol increased (p < 0.001). In the first hour of NMP, glucose and pyruvate increased while glycerol decreased (p < 0.001). After 4 h, all metabolites had returned to baseline. Inflammatory markers C3a, soluble C5b-9, TNF, IL-6, IL-1β, IL-8, and IL-10 increased significantly during NMP in perfusate and kidney tissue. C5-inhibition significantly decreased perfusate and urine soluble C5b-9 (p < 0.001; p = 0.002, respectively), and tissue IL-1β (p = 0.049), but did not alter other inflammatory markers. Microdialysis can accurately monitor the effect of NMP on renal metabolism. Closed-circuit NMP induces inflammation, which appeared partly complement-mediated. Targeting additional immune inhibitors should be the next step.
AB - Normothermic machine perfusion (NMP) is a clinical strategy to reduce renal ischemia-reperfusion injury (IRI). Optimal NMP should restore metabolism and minimize IRI induced inflammatory responses. Microdialysis was used to evaluate renal metabolism. This study aimed to assess the effect of complement inhibition on NMP induced inflammatory responses. Twenty-two pig kidneys underwent 18 h of static cold storage (SCS) followed by 4 h of NMP using a closed-circuit system. Kidneys were randomized to receive a C5-inhibitor or placebo during SCS and NMP. Perfusion resulted in rapidly stabilized renal flow, low renal resistance, and urine production. During SCS, tissue microdialysate levels of glucose and pyruvate decreased significantly, whereas glycerol increased (p < 0.001). In the first hour of NMP, glucose and pyruvate increased while glycerol decreased (p < 0.001). After 4 h, all metabolites had returned to baseline. Inflammatory markers C3a, soluble C5b-9, TNF, IL-6, IL-1β, IL-8, and IL-10 increased significantly during NMP in perfusate and kidney tissue. C5-inhibition significantly decreased perfusate and urine soluble C5b-9 (p < 0.001; p = 0.002, respectively), and tissue IL-1β (p = 0.049), but did not alter other inflammatory markers. Microdialysis can accurately monitor the effect of NMP on renal metabolism. Closed-circuit NMP induces inflammation, which appeared partly complement-mediated. Targeting additional immune inhibitors should be the next step.
KW - inflammation
KW - ischemia-reperfusion injury
KW - microdialysis
KW - normothermic machine perfusion
KW - renal metabolism
UR - http://www.scopus.com/inward/record.url?scp=85210491216&partnerID=8YFLogxK
U2 - 10.3389/ti.2024.13348
DO - 10.3389/ti.2024.13348
M3 - Article
C2 - 39606689
AN - SCOPUS:85210491216
SN - 0934-0874
VL - 37
JO - Transplant International
JF - Transplant International
M1 - 13348
ER -