Benefits of active oxygenation during hypothermic machine perfusion of kidneys in a preclinical model of deceased after cardiac death donors

Thuillier, Raphaël; Allain, Géraldine; Celhay, O.; Hébrard, William; Barrou, B.; Badet, Lionel; Leuvenink, Henri G. D.; Hauet, Thierry

doi:10.1016/j.jss.2013.04.071

Cited by 82 publications

(75 citation statements)

References 28 publications

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“…These MP effects were concomitant to increases in cortical microcirculation after unclamping in vivo. NO synthesis being oxygen-dependent, future studies should investigate this pathway during oxygenated MP, which previously proved more protective than standard MP (51)(52)(53). Moreover, pharmaceutical strategies directed at this pathway could be developed to improve both static and dynamic storage.…”

Section: Discussionmentioning

confidence: 99%

Mechanistic Analysis of Nonoxygenated Hypothermic Machine Perfusion’s Protection on Warm Ischemic Kidney Uncovers Greater eNOS Phosphorylation and Vasodilation

Chatauret

Coudroy

Delpech

et al. 2014

American Journal of Transplantation

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Protection of endothelial cell function may explain the benefits of nonoxygenated hypothermic machine perfusion (MP) for marginal kidney preservation. However, this hypothesis remains to be tested with a preclinical model. We postulated that MP protects the nitric oxide (NO) signaling pathway, altered by static cold storage (CS), and improves renal circulation recovery compared to CS. The endothelium releases the vasodilator NO in response to flow via either increased endothelial NO synthase (eNOS) expression (KLF2-dependent) or activation of eNOS by phosphorylation (via Akt, PKA or AMPK). Using a porcine model of kidney transplantation, including 1 h of warm ischemia and preserved 24 h by CS or MP (n ¼ 5), we reported that MP did not alter the cortical levels of KLF2 and eNOS at the end of preservation, but significantly increased eNOS activating phosphorylation compared to CS. eNOS phosphorylation appeared AMPK-dependent and was concomitant to an increased NO-dependent vasodilation of renal arteries measured, ex situ, at the end of preservation. In vivo, laser Doppler showed that cortical microcirculation was improved at reperfusion in MP kidneys. In conclusion, we demonstrate for the first time, in a large-animal model, that MP protects the NO signaling pathway, confirming the value of MP for marginal kidney preservation.Abbreviations: Akt, protein kinase B; AMPKa, 5 0 -adenosine monophosphate-activated protein kinase alpha; ANOVA, analysis of variance; CS, cold storage; CTL, control; DCD, donation after circulatory death; eNOS, endothelial nitric oxide synthase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; iNOS, inducible nitric oxide synthase; KLF2, Kruppel-like factor 2; L19, ribosomal protein L19; L-NAME, NGnitro-L-arginine methyl ester; MP, machine perfusion; MPS, machine perfusion solution; NO, nitric oxide; PKA, protein kinase A; RPLPO, ribosomal phosphoprotein large P0 subunit; RT-qPCR, reverse transcriptase quantitative polymerase chain reaction; SEM, standard error of the mean; UW, University of Wisconsin; WI-60, 1 h warm ischemia

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Section: Discussionmentioning

confidence: 99%

Mechanistic Analysis of Nonoxygenated Hypothermic Machine Perfusion’s Protection on Warm Ischemic Kidney Uncovers Greater eNOS Phosphorylation and Vasodilation

Chatauret

Coudroy

Delpech

et al. 2014

American Journal of Transplantation

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“…In order to increase the use of less optimal organs for transplantation, aerobic extracorporeal normothermic, subnormothermic, and hypothermic preservation techniques have been developed which demonstrate an improved preservation quality compared to anaerobic preservation for kidney, liver, heart, lung, and pancreas grafts [8,9,10,11,12,13]. The benefit from aerobic preservation has been related to the fact that even at hypothermia, a residual metabolism is operative which has restorative capacities if oxygen is provided [8,14].…”

Section: Introductionmentioning

confidence: 99%

Comparison of Aerobic Preservation by Venous Systemic Oxygen Persufflation or Oxygenated Machine Perfusion of Warm-Ischemia-Damaged Porcine Kidneys

Kalenski

Mancina²,

Paschenda³

et al. 2016

Eur Surg Res

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Background/Aim: The global shortage of donor organs for transplantation has necessitated the expansion of the organ pool through increased use of organs from less ideal donors. Venous systemic oxygen persufflation (VSOP) and oxygenated machine perfusion (OMP) have previously demonstrated beneficial results compared to cold storage (CS) in the preservation of warm-ischemia-damaged kidney grafts. The aim of this study was to compare the efficacy of VSOP and OMP for the preservation of warm-ischemia-damaged porcine kidneys using the recently introduced Ecosol preservation solution compared to CS using Ecosol or histidine-tryptophan-ketoglutarate solution (HTK). Materials and Methods: Kidneys from German Landrace pigs (n = 5/group) were retrieved and washed out with either Ecosol or HTK after 45 min of clamping of the renal pedicle. As controls, kidneys without warm ischemia, cold stored for 24 h in HTK, were employed. Following 24 h of preservation by VSOP, OMP, CS-Ecosol, or CS-HTK, renal function and damage were assessed during 1 h using the isolated perfused porcine kidney model. Results: During reperfusion, urine production was significantly higher in the VSOP and OMP groups than in the CS-HTK group; however, only VSOP could demonstrate lower urine protein concentrations and fractional excretion of sodium, which did not differ from the non-warm-ischemia-damaged control group. VSOP, CS-Ecosol, and controls showed better maintenance of the acid-base balance than CS-HTK. Reduced lipid peroxidation, as reflected in postreperfusion tissue thiobarbituric acid-reactive substance levels, was observed in the VSOP group compared to the OMP group, and the VSOP and CS-Ecosol groups had concentrations similar to the controls. The ratio of reduced to oxidized glutathione was higher in the VSOP, OMP, and CS-Ecosol groups than in the CS-HTK group and controls, with a higher ratio in the VSOP than in the OMP group. Conclusion: VSOP was associated with mitigation of oxidative stress in comparison to OMP and CS. Preservation of warm-ischemia-damaged porcine kidneys by VSOP was improved compared to OMP and CS, and was comparable to preservation of non-warm-ischemia-damaged cold-stored kidneys.

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“…15 However, in the DCD setting, associated with a greater period of warm ischemia, creatinine clearance was higher, 16 peak creatinine levels were lower after kidney transplantation and there was less interstitial fibrosis in the 3-month follow-up when oxygenated MP was applied. 17 This might be explained by the fact that oxygenated MP is more beneficial in organs undergoing a prolonged warm ischemia. 2 It could also explain why in Watson's multicenter randomized controlled trial of DCD-kidney transplantation, using "nonoxygenated" MP no statistically significant reduction in delayed graft function (DGF) could be shown when compared to static CS.…”

Section: The Importance Of Oxygenationmentioning

confidence: 99%

Current perspectives in transplant medicine: hypothermic oxygenated perfusion

Michel¹,

Madsen²

2016

TRRM

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Benefits of active oxygenation during hypothermic machine perfusion of kidneys in a preclinical model of deceased after cardiac death donors

Cited by 82 publications

References 28 publications

Mechanistic Analysis of Nonoxygenated Hypothermic Machine Perfusion’s Protection on Warm Ischemic Kidney Uncovers Greater eNOS Phosphorylation and Vasodilation

Mechanistic Analysis of Nonoxygenated Hypothermic Machine Perfusion’s Protection on Warm Ischemic Kidney Uncovers Greater eNOS Phosphorylation and Vasodilation

Comparison of Aerobic Preservation by Venous Systemic Oxygen Persufflation or Oxygenated Machine Perfusion of Warm-Ischemia-Damaged Porcine Kidneys

Current perspectives in transplant medicine: hypothermic oxygenated perfusion

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