Induction of Organ Dysfunction and Up-Regulation of Inflammatory Markers in the Liver and Kidneys of Hypotensive Brain Dead Rats: A Model to Study Marginal Organ Donors1,2

Hoeven, Joost A. B. van der; Ploeg, Rutger J.; Postema, Folkert; Molema, Grietje; Vos, Paul De; Girbes, Armand R.J.; Suylichem, P.T.R. van; Schilfgaarde, R. van; Horst, Gert J. Ter

doi:10.1097/00007890-199912270-00012

Cited by 108 publications

(73 citation statements)

References 24 publications

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“…The extent of catecholamine release is largely dependent on the tempo and extent of the cerebral insult (Rosner et al 1984, Pratschke et al 2000. In our experiments, the MAP of the peak was 14275 mmHg, which is lower than peak levels observed in the sudden onset model, as has been previously used by our group ( Figure 1B) (van der Hoeven et al 1999). This effect is probably due to the reduced release of catecholamines and the reduced pulmonary changes that are described as being related to catecholamine release (Novitzky et al 1987).…”

Section: Discussionsupporting

confidence: 46%

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The gradual onset brain death model: a relevant model to study organ donation and its consequences on the outcome after transplantation

et al. 2007

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SummaryOrgans used for transplantation are usually derived from heart-beating brain dead donors. However, brain death is known to have negative effects on donor organ quality, previously studied using a difficult to control sudden onset experimental model. We have now developed a reproducible gradual onset brain death model in rats without requiring inotropic support. Fisher inbred rats weighing 260-300 g were used. Brain death was induced by a gradual inflation of a subdurally placed balloon catheter. During induction and the period following brain death, the animals were mechanically ventilated and blood pressure was continuously monitored. The blood pressure registration showed a characteristic pattern during brain death induction, in which a decrease in blood pressure, a hypotensive period in which the Cushing response occurred, and a sharp peak were consistent findings. After brain death was induced, blood pressure was maintained at normotensive levels up to 4 h. After the experiments, neuropathological evaluation of the brain located haemorrhagic cerebral parenchyma, and immunocytochemistry of liver tissue revealed a significant influx of polymorph nuclear cells, as was previously observed as well. This improved model allows the study of brain death on donor organ quality without the use of inotropic support.

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Section: Discussionsupporting

confidence: 46%

“…Our previous sudden onset model resulted in a relatively large number of animals that either died from cardiac arrest or could not be included due to uncontrollable haemodynamic instability (van der Hoeven et al 1999). We have therefore developed a simple, reproducible and clinically relevant animal brain death model in which brain death is gradually induced.…”

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confidence: 99%

The gradual onset brain death model: a relevant model to study organ donation and its consequences on the outcome after transplantation

et al. 2007

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“…The experimental data on gene expression nicely reflect the clinical observation of severe systemic inflammation in brain-dead organ donors. 22,23 We previously identified key members of the inflammation cascade, namely the adhesion molecules, and mitochondrial controllers of apoptosis as being strongly differentially regulated in cadaveric donor organs compared to kidneys from live donors. 3 Cadaveric renal transplant donors often experience hemodynamic instability due to central diabetes insipitus and hormonal misregulation of circulation and massive cytokine release.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide gene-expression patterns of donor kidney biopsies distinguish primary allograft function

Hauser

Schwarz

Mitterbauer

et al. 2004

Laboratory Investigation

109

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Roughly 25% of cadaveric, but rarely living donor renal transplant recipients, develop postischemic acute renal failure, which is a main risk factor for reduced long-term allograft survival. An accurate prediction of recipients at risk for ARF is not possible on the basis of donor kidney morphology or donor/recipient demographics. We determined the genome-wide gene-expression pattern using cDNA microarrays in three groups of 36 donor kidney wedge biopsies: living donor kidneys with primary function, cadaveric donor kidneys with primary function and cadaveric donor kidneys with biopsy proven acute renal failure. The descriptive genes were characterized in gene ontology terms to determine their functional role. The validation of microarray experiments was performed by real-time PCR. We retrieved 132 genes after maxT adjustment for multiple testing that significantly separated living from cadaveric kidneys, and 48 genes that classified the donor kidneys according to their post-transplant course. The main functional roles of these genes are cell communication, apoptosis and inflammation. In particular, members of the complement cascade were activated in cadaveric, but not in living donor kidneys. Thus, suppression of inflammation in the cadaveric donor might be a cheap and promising intervention for postischemic acute renal failure.

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“…Under hemodynamic and rheological unstable conditions, endothelial cells have demonstrated their ability to sense variations in mechanical forces, such as shear stress, that appear as a consequence of blood flow and viscosity alterations (4,5). Numerous studies suggest that immune activation with increased endothelial cell activation and immediate early gene expression occurs after BD induction (6)(7)(8)(9). Moreover, the expression of endothelial adhesion molecules ICAM-1 and VCAM-1 and the influx of leukocytes in the kidney are shown to occur faster and be more profound when hemodynamic instability in the brain dead donor is not corrected (10).…”

Section: Introductionmentioning

confidence: 99%

Early Events in Kidney Donation: Progression of Endothelial Activation, Oxidative Stress and Tubular Injury After Brain Death

Morariu

Schuurs

Leuvenink

et al. 2008

American Journal of Transplantation

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Cerebral injury leading to brain death (BD) causes major physiologic derangements in potential organ donors, which may result in vascular-endothelial activation and affect posttransplant graft function. We investigated the kinetic of pro-coagulatory and proinflammatory endothelial activation and the subsequent oxidative stress and renal tubular injury, early after BD declaration. BD was induced by slowly inflating a balloon-catheter inserted in the extradural space over a period of 30 min. Rats (n = 30) were sacrificed 0.5, 1, 2 or 4 h after BD-induction and compared with sham-controls. This study demonstrates immediate pro-coagulatory and pro-inflammatory activation of vascular endothelium after BD in kidney donor rats, proportional with the duration of BD. E-and P-Selectins, Aa /Bb -fibrinogen mRNA were abruptly and progressively up-regulated from 0.5 h BD onwards; P-Selectin membrane protein expression was increased; fibrinogen was primarily visualized in the peritubular capillaries. Plasma von Willebrand factor was significantly higher after 2 h and 4 h BD. Urine heart-fatty-acid-binding-protein and Nacetyl-glucosaminidase, used as new specific and sensitive markers of proximal and distal tubular damage, were found significantly increased after 0.5 h, with a maximum at 4 h. Unexpectedly, oxidative stress was detectable only late, after the installation of tubular injury, suggesting only a secondary role for hypoxia in triggering these injuries.

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Induction of Organ Dysfunction and Up-Regulation of Inflammatory Markers in the Liver and Kidneys of Hypotensive Brain Dead Rats: A Model to Study Marginal Organ Donors1,2

Cited by 108 publications

References 24 publications

The gradual onset brain death model: a relevant model to study organ donation and its consequences on the outcome after transplantation

The gradual onset brain death model: a relevant model to study organ donation and its consequences on the outcome after transplantation

Genome-wide gene-expression patterns of donor kidney biopsies distinguish primary allograft function

Early Events in Kidney Donation: Progression of Endothelial Activation, Oxidative Stress and Tubular Injury After Brain Death

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