Liver transplantation from non-heart-beating donors: Current status and future prospects

Reddy, Srikanth; Zilvetti, Miguel; Brockmann, Jens; McLaren, Andrew; Friend, Peter J.

doi:10.1002/lt.20268

Cited by 103 publications

(85 citation statements)

References 70 publications

(71 reference statements)

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“…The fundamental problem with CD organs is prolonged warm ischemia. Organ preservation and transplantation is associated with ischemia-reperfusion (IR) injury (Reddy et al 2004). Warm ischemia depletes oxygen in cells, thereby reducing intracellular adenosine triphosphate (ATP) levels.…”

Section: Introductionmentioning

confidence: 99%

“…Warm ischemia depletes oxygen in cells, thereby reducing intracellular adenosine triphosphate (ATP) levels. ATP depletion leads to pump disarmament, causing the loss of electrolyte gradients and membrane integrity, which in turn promotes cellular edema and sinusoidal narrowing (Carini et al 1999;Reddy et al 2004). Thus, warm ischemia causes sinusoidal microcirculatory disturbances after reperfusion (Reddy et al 2004).…”

Section: Introductionmentioning

confidence: 99%

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Soluble Thrombomodulin Ameliorates Ischemia-Reperfusion Injury of Liver Grafts by Modulating the Proinflammatory Role of High-Mobility Group Box 1

Kashiwadate

Miyagi

Hara

et al. 2016

Tohoku J. Exp. Med.

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Transplantation using grafts obtained after cardiac death (CD) is considered a promising solution for graft shortages. However, no standard criteria for organ preservation have been established for CD donors. High-mobility group box 1 (HMGB1) is a DNA-binding protein that is released from dying hepatocytes as an early mediator of inflammation and organ tissue damage. HMGB1 stimulates immunocytes to produce inflammatory cytokines, thereby amplifying the inflammatory response. Thrombomodulin is an integral membrane protein that functions as an endothelial anticoagulant cofactor, and it binds HMGB1 through the extracellular domain. We investigated the effects of ART-123, recombinant human soluble thrombomodulin, on warm ischemia-reperfusion injury in liver grafts. Male Wistar rats were divided into four ex vivo groups: heart-beating (HB) group, in which livers were isolated from HB donors; CD group, in which livers were isolated from CD donors exposed to apnea-induced conditions and warm ischemic conditions for 30 min after cardiac arrest; and two CD groups pretreated with ART-123 (1 or 5 mg/kg). Each isolated liver was reperfused for 1 h after cold preservation for 6 h. The perfusate levels of HMGB1, LDH, TNF-α, and IL-6 were significantly lower in the CD group pretreated with ART-123 (5 mg/kg) than in the CD group. Bile production was significantly higher in the CD group pretreated with ART-123 (5 mg/kg) than in the CD group. The sinusoidal spaces were significantly narrower in the CD group than in the other groups. We propose that ART-123 maintains sinusoidal microcirculation by reducing endothelial cell damage during warm ischemia-reperfusion injury.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Soluble Thrombomodulin Ameliorates Ischemia-Reperfusion Injury of Liver Grafts by Modulating the Proinflammatory Role of High-Mobility Group Box 1

Kashiwadate

Miyagi

Hara

et al. 2016

Tohoku J. Exp. Med.

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“…However, I/R injury is the underpinning of graft dysfunction that is seen in the marginal organ (Busuttil & Tanaka, 2003). The fundamental problem with NHBD organs is the prolonged warm ischemia before cold preservation (Reddy et al, 2004). Controlled NHBDs provide organs that are far less prone to ischemic damage and tend to offer superior posttransplant function (Busuttil & Tanaka, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…Controlled NHBDs provide organs that are far less prone to ischemic damage and tend to offer superior posttransplant function (Busuttil & Tanaka, 2003). The use of uncontrolled NHBDs is associated with a very high risk of primary nonfunction (Reddy et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Ischemia-Reperfusion Injury Associated with Liver Transplantation in 2011: Past and Future

Elias-Miró¹,

Jiménez‐Castro²,

Peralta³

2012

Liver Transplantation - Basic Issues

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“…However, conventional with simple cold storage (SCS) of these DCD livers is associated with a higher risk of primary non-function and delayed graft failure (1)(2)(3). Normothermic Extracorporeal Liver Perfusion (NELP) has been suggested as an alternative (1)(2)(3).…”

mentioning

confidence: 99%

Sequential Cold Storage and Normothermic Perfusion of the Ischemic Rat Liver

Tolboom

Milwid

Izamis

et al. 2008

Transplantation Proceedings

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Extending transplant criteria to include livers obtained from donor after cardiac death (DCD) could increase the liver donor pool, but conventional simple cold storage of these ischemic organs can lead to poor graft function after transplantation. Experimental normothermic machine perfusion has previously proven to be useful for the recovery and preservation of DCD livers, but it is more complicated than conventional cold storage, and is therefore perhaps not practical during the entire preservation period. In clinical situations, the combined use of simple cold storage and normothermic perfusion preservation of DCD livers might be more realistic, but even a brief period of cold storage prior to normothermic preservation has been suggested to have a negative impact on graft viability. In this study we show that rat livers subjected to 45 minutes of ex-vivo warm ischemia followed by 2 hours of simple cold storage can be reclaimed by 4 hours of normothermic machine perfusion. These livers could be orthotopically transplanted into syngeneic recipients with 100% survival after 4 weeks (N=10), similar to the survival of animals that received fresh livers that were stored on ice in University of Wisconsin (UW) solution for 6 hours (N=6). On the other hand, rats that received ischemic livers preserved on ice in UW solution for 6 hours (N = 6) all died within 12 hours after transplantation. These results suggest that normothermic perfusion can be used to reclaim DCD livers subjected to an additional period of cold ischemia during hypothermic storage.The current shortage of suitable donor livers could be significantly alleviated by extending liver graft criteria to include livers obtained from donors after cardiac death (DCD). However, conventional with simple cold storage (SCS) of these DCD livers is associated with a higher risk of primary non-function and delayed graft failure (1-3). Normothermic Extracorporeal Liver Perfusion (NELP) has been suggested as an alternative (1-3). However, if machine perfusion of donor organs is to be realized clinically, a brief period of static cold storage between donor organ recovery and normothermic preservation is desirable. This period would enable the recovery of the organ as usual, after which it could be transported to a specialized transplantation center, where subsequent recovery of the organ with NELP can occur. The addition of an initial period of SCS prior to NELP, however, has been suggested to negatively impact the viability of these DCD grafts due to their increased sensitivity to cold ischemia (4,5). To assess the feasibility of this hybrid approach, we have evaluated post-operative graft function of orthotopically transplanted ischemic rat livers that were preserved with a combination of cold storage in University of Wisconsin (UW) solution and normothermic Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscrip...

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Liver transplantation from non-heart-beating donors: Current status and future prospects

Cited by 103 publications

References 70 publications

Soluble Thrombomodulin Ameliorates Ischemia-Reperfusion Injury of Liver Grafts by Modulating the Proinflammatory Role of High-Mobility Group Box 1

Soluble Thrombomodulin Ameliorates Ischemia-Reperfusion Injury of Liver Grafts by Modulating the Proinflammatory Role of High-Mobility Group Box 1

Ischemia-Reperfusion Injury Associated with Liver Transplantation in 2011: Past and Future

Sequential Cold Storage and Normothermic Perfusion of the Ischemic Rat Liver

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