A Biphasic Response to Nitric Oxide Donation in an Ex Vivo Model of Donation After Cardiac Death Renal Transplantation

Yates, P.; Hosgood, Sarah A.; Nicholson, Michael L.

doi:10.1016/j.jss.2011.03.073

Cited by 13 publications

(9 citation statements)

References 27 publications

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“…erythropoietin, adenosine and verapamil, against short courses of warm renal IRI has been reported [ 10 -12,22,30 -33 ] . As with the other two members of the small molecule family, H 2 S has also been shown to possess bimodal effects: at lower concentrations it is cytoprotective by inducing a hypometabolic state via a myriad of mechanisms including alterations of the electron transport chain, whereas at higher levels it is toxic and leads to cell injury and death [ 21,34,35 ] . Similar to other reports, we showed that H 2 S was protective in renal IRI and preserved renal function ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Detrimental effects of prolonged warm renal ischaemia‐reperfusion injury are abrogated by supplemental hydrogen sulphide: an analysis using real‐time intravital microscopy and polymerase chain reaction

Zhu¹,

Kalbfleisch²,

Yang³

et al. 2012

BJU International

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What's known on the subject? and What does the study add?Hydrogen sulphide (H2S) has recently been classified as a member of the gasotransmitter family. Its physiological and pathophysiological effects are rapidly expanding with numerous studies highlighting the protective effects of H2S on ischaemia‐reperfusion injury (IRI) in various organ systems, e.g. heart, liver, CNS and lungs. The mechanisms behind its protective effects reside in its vasodilatory, anti‐inflammatory and anti‐oxidant characteristics. These specific mechanistic profiles appear to be different across different tissues and models of IRI.We recently showed that supplementation of preservation solutions with H2S during periods of prolonged cold renal storage and subsequent renal transplantation leads to a massive and significant survival, functional and tissue protective advantage compared with storage in standard preservation solution alone. However, there have only been a few studies that have evaluated the effects of H2S against warm renal IRI; although these studies have focused primarily upon shorter periods of warm renal pedicle clamping, they have shown a clear survival benefit to H2S supplementation. The present study adds to the existing literature by evaluating the effects of H2S in a model of warm IRI with clinically relevant, prolonged warm ischaemia‐reperfusion times (1 h ischaemia, 2 h reperfusion). We show an unprecedented view into real‐time renal and hepatic perfusion with intravital microscopy throughout the reperfusion period. We show, for the first time, that supplemental H2S has multiple protective functions against the warm IRI‐induced tissue damage, which may be clinically applicable to both donation after cardiac death models of renal transplantation, as well as to uro‐oncological practices requiring surgical clamping of the renal pedicle, e.g. during a partial nephrectomy.OBJECTIVE To determine the protective role of supplemental hydrogen sulphide (H2S) in prolonged warm renal ischaemia‐reperfusion injury (IRI) using real‐time intravital microscopy (IVM). MATERIALS AND METHODS Uninephrectomised Lewis rats underwent 1 h of warm ischaemia and 2 h of reperfusion during intraperitoneal treatment with phosphate buffer saline (IRI, n= 10) or 150 µmol/L NaHS (IRI+H2S, n= 12) and were compared with sham‐operated rats (n= 9). Blood was collected for measurement of serum creatinine (Cr), alanine aminotransferase (ALT) and aspartate aminotransferase (AST). IVM was performed to assess renal and hepatic microcirculation. Kidneys were sectioned for histology and real‐time quantitative polymerase chain reaction for markers of inflammation. RESULTS The mean (sd) Cr concentration raised to 72.8 (2.5) µmol/L after IRI from 11.0 (0.7) µmol/L (sham) but was partially inhibited with H2S to 62.8 (0.9) µmol/L (P < 0.05). H2S supplementation during IRI increased renal capillary perfusion on IVM, and improved acute tubular necrosis and apoptotic scores on histology (P < 0.05). Supplemental H2S decreased expression of the pro‐inflammatory markers toll‐like receptor 4, tumour necrosis factor α, interleukin 8, C‐C chemokine receptor type 5, interferon γ and interleukin 2 (P < 0.05). Distant organ (liver) dysfunction after renal IRI was limited with H2S supplementation: blunting of the ALT and AST surge, decreased hepatic sinusoidal vasodilation, and decreased leukocyte infiltration in post‐sinusoidal venules (P < 0.05). H2S supplementation directly inhibited interleukin 8‐induced neutrophil chemotaxis in vitro (P < 0.05). CONCLUSIONS These findings are the first to show the real‐time protective role of supplemental H2S in prolonged periods of warm renal IRI, perhaps acting by decreasing leukocyte migration and limiting inflammatory responses. The protective effects of H2S suggest potential clinical applications in both donors after cardiac death models of renal transplantation and oncological practices requiring vascular clamping.

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Section: Discussionmentioning

confidence: 99%

Detrimental effects of prolonged warm renal ischaemia‐reperfusion injury are abrogated by supplemental hydrogen sulphide: an analysis using real‐time intravital microscopy and polymerase chain reaction

Zhu¹,

Kalbfleisch²,

Yang³

et al. 2012

BJU International

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“…During NMP, in both groups a nutrient mixture was infused including amino acids, glucose, insulin and sodium bicarbonate ( online supplementary table 1 ). Of the compounds added before and during NMP, nitroprusside was given as vasodilator to increase renal blood flow, 16 mannitol was given to decrease cellular swelling, 17 while leukocytes were filtered out of the blood and dexamethasone was administered, respectively, to decrease the inflammatory response. 18 These compounds are proposed as preservation strategy surrounding kidney transplantation to reduce ischemia-reperfusion injury, 19 and have been deemed necessary to support perfusion and renal function when establishing our NMP model (non-published data).…”

Section: Methodsmentioning

confidence: 99%

Increasing metformin concentrations and its excretion in both rat and porcine ex vivo normothermic kidney perfusion model

Posma

Venema

Huijink

et al. 2020

BMJ Open Diab Res Care

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IntroductionMetformin can accumulate and cause lactic acidosis in patients with renal insufficiency. Metformin is known to inhibit mitochondria, while renal secretion of the drug by proximal tubules indirectly requires energy. We investigated whether addition of metformin before or during ex vivo isolated normothermic machine perfusion (NMP) of porcine and rat kidneys affects its elimination.Research design and methodsFirst, Lewis rats were pretreated with metformin or saline the day before nephrectomy. Subsequently, NMP of the kidney was performed for 90 min. Metformin was added to the perfusion fluid in one of three different concentrations (none, 30 mg/L or 300 mg/L). Second, metformin was added in increasing doses to the perfusion fluid during 4 hours of NMP of porcine kidneys. Metformin concentration was determined in the perfusion fluid and urine by liquid chromatography-tandem mass spectrometry.ResultsMetformin clearance was approximately 4–5 times higher than creatinine clearance in both models, underscoring secretion of the drug. Metformin clearance at the end of NMP in rat kidneys perfused with 30 mg/L was lower than in metformin pretreated rats without the addition of metformin during perfusion (both p≤0.05), but kidneys perfused with 300 mg/L trended toward lower metformin clearance (p=0.06). Creatinine clearance was not different between treatment groups. During NMP of porcine kidneys, metformin clearance peaked at 90 min of NMP (18.2±13.7 mL/min/100 g). Thereafter, metformin clearance declined, while creatinine clearance remained stable. This observation can be explained by saturation of metformin transporters with a Michaelis-Menten constant (95% CI) of 23.0 (10.0 to 52.3) mg/L.ConclusionsMetformin was secreted during NMP of both rat and porcine kidneys. Excretion of metformin decreased under increasing concentrations of metformin, which might be explained by saturation of metformin transporters rather than a self-inhibitory effect. It remains unknown whether a self-inhibitory effect contributes to metformin accumulation in humans with longer exposure times.

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“…The Leicester group used an ex vivo porcine model of kidney transplantation to compare the effects of reperfusion with and without nitric oxide supplementation on initial renal blood flow and function. Nitric oxide supplementation during initial reperfusion of DCD kidneys improves renal blood flow but should be considered with caution due to potential deleterious effects of accumulated nitrogenous free radicals which may impair renal blood flow [57] . Sola et al [58] studied the incidence of DGF in a group of 3365 renal transplant recipient patients from various Spanish centres noting that the incidence of DGF remained constant in the 3 years studied (30.4%, 30.8% and 29.2%, respectively).…”

Section: Dgf and Primary Non Functionmentioning

confidence: 99%

Kidney donation after cardiac death

Akoh¹

2012

WJN

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There is continuing disparity between demand for and supply of kidneys for transplantation. This review describes the current state of kidney donation after cardiac death (DCD) and provides recommendations for a way forward. The conversion rate for potential DCD donors varies from 40%-80%. Compared to controlled DCD, uncontrolled DCD is more labour intensive, has a lower conversion rate and a higher discard rate. The super-rapid laparotomy technique involving direct aortic cannulation is preferred over in situ perfusion in controlled DCD donation and is associated with lower kidney discard rates, shorter warm ischaemia times and higher graft survival rates. DCD kidneys showed a 5.73-fold increase in the incidence of delayed graft function (DGF) and a higher primary non function rate compared to donation after brain death kidneys, but the long term graft function is equivalent between the two. The cold ischaemia time is a controllable factor that significantly influences the outcome of allografts, for example, limiting it to < 12 h markedly reduces DGF. DCD kidneys from donors < 50 function like standard criteria kidneys and should be viewed as such. As the majority of DCD kidneys are from controlled donation, incorporation of uncontrolled donation will expand the donor pool. Efforts to maximise the supply of kidneys from DCD include: implementing organ recovery from emergency department setting; improving family consent rate; utilising technological developments to optimise organs either prior to recovery from donors or during storage; improving organ allocation to ensure best utility; and improving viability testing to reduce primary non function.

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A Biphasic Response to Nitric Oxide Donation in an Ex Vivo Model of Donation After Cardiac Death Renal Transplantation

Cited by 13 publications

References 27 publications

Detrimental effects of prolonged warm renal ischaemia‐reperfusion injury are abrogated by supplemental hydrogen sulphide: an analysis using real‐time intravital microscopy and polymerase chain reaction

Detrimental effects of prolonged warm renal ischaemia‐reperfusion injury are abrogated by supplemental hydrogen sulphide: an analysis using real‐time intravital microscopy and polymerase chain reaction

Increasing metformin concentrations and its excretion in both rat and porcine ex vivo normothermic kidney perfusion model

Kidney donation after cardiac death

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