Mitochondrial membrane potential and delayed graft function following kidney transplantation

Lonze, Bonnie E.; Ruck, Jessica M.; Luo, Xiaobin; Massie, Allan B.; Melancon, Keith; Burdick, James F.; Segev, Dorry L.; Sun, Zhaoli

doi:10.1111/ajt.15174

Cited by 11 publications

(9 citation statements)

References 23 publications

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“…In contrast, non-hibernator cells show loss of membrane potential, decreased ATP and increased MDA levels, similar to the results in this study [46]. Others have shown that lower MMP can be associated with an increased risk of delayed graft function after kidney transplantation [47]. In addition to hibernation, the effects of gasotransmitters H 2 S, CO and NO, have been shown to decrease ROS formation, potentially via mitochondria [48–50].…”

Section: Discussionsupporting

confidence: 83%

Renal temperature reduction progressively favors mitochondrial ROS production over respiration in hypothermic kidney preservation

et al. 2019

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Background Hypothermia, leading to mitochondrial inhibition, is widely used to reduce ischemic injury during kidney preservation. However, the exact effect of hypothermic kidney preservation on mitochondrial function remains unclear. Methods We evaluated mitochondrial function [i.e. oxygen consumption and production of reactive oxygen species (ROS)] in different models (porcine kidney perfusion, isolated kidney mitochondria, and HEK293 cells) at temperatures ranging 7–37 °C. Results Lowering temperature in perfused kidneys and isolated mitochondria resulted in a rapid decrease in oxygen consumption (65% at 27 °C versus 20% at 7 °C compared to normothermic). Decreased oxygen consumption at lower temperatures was accompanied by a reduction in mitochondrial ROS production, albeit markedly less pronounced and amounting only 50% of normothermic values at 7 °C. Consequently, malondialdehyde (a marker of ROS-induced lipid peroxidation) accumulated in cold stored kidneys. Similarly, low temperature incubation of kidney cells increased lipid peroxidation, which is due to a loss of ROS scavenging in the cold. Conclusions Lowering of temperature highly affects mitochondrial function, resulting in a progressive discrepancy between the lowering of mitochondrial respiration and their production of ROS, explaining the deleterious effects of hypothermia in transplantation procedures. These results highlight the necessity to develop novel strategies to decrease the formation of ROS during hypothermic organ preservation. Electronic supplementary material The online version of this article (10.1186/s12967-019-2013-1) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 83%

Renal temperature reduction progressively favors mitochondrial ROS production over respiration in hypothermic kidney preservation

et al. 2019

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“…Mitochondria are the site of ATP synthesis, intracellular calcium homeostasis, and ROS levels, and can regulate the cell cycle control. In DGF, there is an important dysfunction of mitochondria that may induce tubular injury and chronic renal damage [ 98 ]. Nephrons are rich in mitochondria that oxidize fatty acids to produce ATP.…”

Section: Dgf and Chronic Graft Dysfunctionmentioning

confidence: 99%

Delayed Graft Function in Kidney Transplant: Risk Factors, Consequences and Prevention Strategies

Ponticelli¹,

Reggiani

Moroni

2022

JPM

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Background. Delayed graft function is a frequent complication of kidney transplantation that requires dialysis in the first week posttransplant. Materials and Methods. We searched for the most relevant articles in the National Institutes of Health library of medicine, as well as in transplantation, pharmacologic, and nephrological journals. Results. The main factors that may influence the development of delayed graft function (DGF) are ischemia–reperfusion injury, the source and the quality of the donated kidney, and the clinical management of the recipient. The pathophysiology of ischemia–reperfusion injury is complex and involves kidney hypoxia related to the duration of warm and cold ischemia, as well as the harmful effects of blood reperfusion on tubular epithelial cells and endothelial cells. Ischemia–reperfusion injury is more frequent and severe in kidneys from deceased donors than in those from living donors. Of great importance is the quality and function of the donated kidney. Kidneys from living donors and those with normal function can provide better results. In the peri-operative management of the recipient, great attention should be paid to hemodynamic stability and blood pressure; nephrotoxic medicaments should be avoided. Over time, patients with DGF may present lower graft function and survival compared to transplant recipients without DGF. Maladaptation repair, mitochondrial dysfunction, and acute rejection may explain the worse long-term outcome in patients with DGF. Many different strategies meant to prevent DGF have been evaluated, but only prolonged perfusion of dopamine and hypothermic machine perfusion have proven to be of some benefit. Whenever possible, a preemptive transplant from living donor should be preferred.

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“…IRI leads, via mitochondrial failure, to cell death, inflammation[5] and fibrosis[6]. In addition, mitochondrial dysfunction might be a surrogate for tissue health after transplantation[7]. Therefore, targeting mitochondria in order to reduce IRI improves preservation of these organs[8].…”

Section: Introductionmentioning

confidence: 99%

Hydrogen sulphide-induced hypometabolism in human-sized porcine kidneys

et al. 2019

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BackgroundSince the start of organ transplantation, hypothermia-forced hypometabolism has been the cornerstone in organ preservation. Cold preservation showed to protect against ischemia, although post-transplant injury still occurs and further improvement in preservation techniques is needed. We hypothesize that hydrogen sulphide can be used as such a new preservation method, by inducing a reversible hypometabolic state in human sized kidneys during normothermic machine perfusion.MethodsPorcine kidneys were connected to an ex-vivo isolated, oxygen supplemented, normothermic blood perfusion set-up. Experimental kidneys (n = 5) received a 85mg NaHS infusion of 100 ppm and were compared to controls (n = 5). As a reflection of the cellular metabolism, oxygen consumption, mitochondrial activity and tissue ATP levels were measured. Kidney function was assessed by creatinine clearance and fractional excretion of sodium. To rule out potential structural and functional deterioration, kidneys were studied for biochemical markers and histology.ResultsHydrogen sulphide strongly decreased oxygen consumption by 61%, which was associated with a marked decrease in mitochondrial activity/function, without directly affecting ATP levels. Renal biological markers, renal function and histology did not change after hydrogen sulphide treatment.ConclusionIn conclusion, we showed that hydrogen sulphide can induce a controllable hypometabolic state in a human sized organ, without damaging the organ itself and could thereby be a promising therapeutic alternative for cold preservation under normothermic conditions in renal transplantation.

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Mitochondrial membrane potential and delayed graft function following kidney transplantation

Cited by 11 publications

References 23 publications

Renal temperature reduction progressively favors mitochondrial ROS production over respiration in hypothermic kidney preservation

Renal temperature reduction progressively favors mitochondrial ROS production over respiration in hypothermic kidney preservation

Delayed Graft Function in Kidney Transplant: Risk Factors, Consequences and Prevention Strategies

Hydrogen sulphide-induced hypometabolism in human-sized porcine kidneys

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