The influence of brain death on donor liver and the potential mechanisms of protective intervention

Abstract

Brain-dead donors have become one of the main sources of organs for transplantation in Western countries. The quality of donor organs is closely related to the outcome of the transplantation. Experimental studies have confirmed the inferior graft survival of livers from brain-dead donors compared with those from living donors. Studies conducted in the past 10 years have shown that brain death is associated with effects on the decreased donor organ quality. However, whether the decrease in the viability of donor organs is caused by brain death or by the events before and after brain death remains uncertain. The purpose of this review is to introduce the advances and controversies regarding the influence of brain death on the viability of donor livers and to summarize the mechanisms of the different protective interventions for donor livers.

Keywords

brain death / donor liver

Introduction

Since the advent of experimental therapies in the 1960s and 1970s, organ transplantation has become an effective and widely used treatment for end-stage organ diseases. The outcomes of transplantation have improved with the development of surgical techniques, development of new types of immunosuppressive agents, and control of postoperative complications. However, keeping the patient complication-free after transplantation and extending his or her survival are met with many difficulties. One of the predominant effective factors is the inherent qualities of the donors themselves. A report released by the China Liver Transplant Registry showed that the number of registered liver transplantations performed from January 1, 1993 to July 12, 2010 is 18 127, far lower than the number of patients who wait for liver transplantation. The shortage of donors and the increasing number of patients have directly caused the use of suboptimal donors in liver transplantation [1]. Living-donor liver transplantation is an effective way to expand the donor pool, but this modality is still in its initial stage in China. There are still many difficulties for the extensive development of adult-to-adult living donor liver transplantation.

Since the first brain-dead donor organ transplantation by a team of French and Belgian surgeons in the 1960s, brain-dead organ donors have gradually become one of the main sources of donor organs in Western countries. Many developed countries have acknowledged brain death as the definition of legal death, and issued laws to guarantee its clinical diagnosis. The Diagnosis Criterion of Brain Death and Judgment Specification of Brain Death (Exposure Draft) enacted by China’s Ministry of Health have defined brain death, which was published in the Chinese Medical Journal. As brain death is a complex issue that involves medical, ethical, legal, and sociological considerations, there are still many concerns that hinder legislation determining brain death in China, and the studies related to brain death are still in their experimental stage.

Research shows that brain death—a dynamic pathologic and physiologic process—is harmful to donors, which provokes hemodynamic, neurologic, endocrine, and immunologic changes, among others [2-5]. This paper reviews Chinese and international research regarding the negative effects of brain death on the liver of potential organ donors, and the different interventions being investigated to prevent this problem.

Adverse Effects of Brain Death

Changes in Hemodynamics

Hemodynamic changes caused by brain death are easily observed and connected with progressive cerebrospinal ischemia. In its initial stage, intracranial pressure increases due to cerebral ischemia and parasympathetic nerves are excited, resulting in a gradual decrease in blood pressure and heart rate. When the ischemia reaches the medulla oblongata, the sympathetic nerves are excited, which causes the explosive release of endogenous catecholamines, vasoconstriction, augmentation of vascular resistance, abrupt elevation of blood pressure, and tachycardia. This is called “sympathetic or catecholamine storm.” There is a marked increase in the levels of epinephrine, norepinephrine, and dopamine in the serum. The release of abundant catecholamines and increased vascular resistance increases the heart load and oxygen consumption. High levels of catecholamines may also lead to intracellular calcium overload, followed by the activation of lipase, proteinase, endonuclease, and nitric oxide synthase, as well as disruption of ATP synthesis, which causes overproduction oxygen free radicals and cell injury. Subsequently, when the catecholamine levels are below baseline and the vascular tension decreases after cerebral herniation, there is a gradual depletion of sympathetic nerves, which leads to hypotension, cardiac dysfunction, and heart failure. This also causes intense vasoconstrictions in the abdominal organs. Although perfusion pressure increases, organ perfusion is markedly reduced. In 1996, Novitzky et al. [6] reported that the vascular resistance in the liver and kidneys doubled and quadrupled, respectively, in brain-dead rats. Other studies have also reported that catecholamines play a very important role in the cardiac damage caused by brain death [7-9]. Furthermore, the faster the onset of brain death, the higher the peak values of catecholamines and the more serious the myocardial damaged [10,11]. A recent study indicated that despite severe hypotension induced by the sudden increase in intracranial pressure, the systemic and splanchnic blood flows are partially preserved without signs of severe hypoperfusion [12].

Changes in inflammatory and immunological aspects

Experimental and clinical reports have shown that brain death causes a series of immunologic and inflammatory changes. The expression of adhesion molecules, inflammatory lymphokines (TNF-α, IFN-γ, interleukin, etc.), and MHC class I and class II molecules within the organs of the brain-dead donor increases. However, the long-term influence of cytokines and their production on transplantation still needs further observation. Van der Hoeven et al. [1] reported that the expression of vascular cell adhesion molecule 1 (VCAM-1) and inter-cellular adhesion molecule 1 (ICAM-1) in the liver of brain-dead donors increases, which augments immune activation and causes leukocyte infiltration in the hepatocytes. This result is identical to that of Steinhoff et al. [13-16]. Kueceuk et al. [17] and Olinga et al. [18] reported that the levels of proinflammatory cytokines interleukin-6 (IL-6) and IL-10 in the liver of brain-dead donors before incision are higher than those of living donors. In addition, the expression levels of IL-6 and IL-10 in tissues and in the serum are relevant, which demonstrates that IL-10 is produced mainly by Kupffer cells in liver and that brain death induces the activation of Kupffer cells. The evident increase in IL-1β may be related to the activation of endothelial cells. Weiss et al. [19] reported that through the real-time reverse transcriptase–polymerase chain reaction (RT-PCR) analysis of the liver tissues from brain-dead donors, the expression levels of macrophage inflammatory proteins-1α (MIP-1α), tumor necrosis factor-α (TNF-α), IL-4, Interferon-γ (IFN-γ), and transforming growth factor-α (TGF-α) mRNA before incision were significantly higher than those of living donors. In particular, the level of IL-6 in brain-dead patients was 5.6 times higher than that of living donors, and this increases gradually over time. As direct evidence of the increase in lymphocyte infiltration, the expression of CD3 and CD25 mRNA increases, especially in two time points—immediately after laparotomy and before preservation—which shows that the CD3+ lymphocyte and CD25 cells increase before transplantation and the expression of major histocompatibility complex-II (MHC-II) cells in brain-dead donors also increases. At 6 months after transplantation, acute postoperative rejection rate of organs from brain-dead donors is 25% compared with 15% for organs from living donors (P = 0.040). At 24 months, acute postoperative rejection rates increase to 38% and 28% for organs from brain-dead and living donors, respectively (P = 0.041). A research conducted by our group [20] reported that the serum levels of TNF-α and IL-6, as well as the expression of ICAM-1, MCP-1, and MHC-II mRNA in the hepatic tissue of brain-dead donors are higher than those of non-brain-dead donors (P<0.05). Pratschke et al. [21] also reported that a maximal immunologic activation of the graft at the end of surgical organ harvesting procedure and Cytokine levels in organs from brain dead donors did not further increase after reperfusion during the engraftment procedure, which was identical to recent observations. Compared with living donors, platelet aggregation and neutrophil infiltration is more common in brain-dead donors.

Apoptosis-regulating Genes

In 2003, using the rat brain-dead model and analysis of the apoptosis-regulating proteins of donor livers, Van der Hoeven et al. [22] found that the number of apoptotic cells, caspase-3 activity, and the mRNA level of all NF-kB-induced activators (Fas, bid) and inhibitors (A1, BCl-xl, and cIAP2) are significantly increased in the liver tissues of brain-dead donors compared with living donors. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining revealed that the apoptotic cells were primarily hepatocytes, which corresponds with the increase in caspase activity. The mechanism of hepatocyte apoptosis is related with the death receptor and mitochondrial pathways. The result of this report is identical with that of Pérez López et al. in 2008 [23], which investigated the expression of apoptosis-regulating genes in brain-dead donohearts. The presence of inflammation and induction of apoptosis may explain the rapid organ dysfunction seen after brain death. Both abnormalities may play a role in the organ dysfunction associated with brain death [24]. The possible effects of apoptosis on the reduction of donor viability and postoperative organ dysfunction have been shown in multiple experiments [25,26], demonstrating that anti-apoptotic treatment before transplantation may prevent or alleviate the organ damage caused by brain death.

Changes in Liver Morphology

Morphological changes in the liver following brain death are even less defined. By observing the liver morphology of brain-dead patients for 48 days in 1989, Nagareda et al. [27] found that there were no obvious changes (e.g., central fibrosis, fatty metamorphosis, piecemeal necrosis, and periportal necrosis) in the first few days, except a wide distribution of central venous congestion and occasional intrahepatic cholangiti. In 1997, Novitzky et al. [28] observed scattered mitochondrial injury, cell necrosis, and loss of glycogen through electron microscopy. In their 2001 study of rat liver transplant models, Van der Hoeven et al. [29] established rat liver transplantation models in 2001; histological examination showed the formation of vacuoles with moderate neutrophilic infiltration in the hepatocytes of brain-dead donor livers after cold preservation before transplantation. Central and marginal necrosis and more severe vacuolation were observed after transplantation. Okamoto et al. [30] and Lin et al. [31], using brain-dead dog models, observed that the liver can tolerate hypotension and that the influence of hemodynamic changes caused by brain death on liver morphology was greater compared with its effect on liver function. In 2003, Toyama et al. [32] found that the permeability and integrity of the cell membrane of brain-dead donor livers are altered. In the same year, Jessem et al. [33] found that leukocyte infiltration of brain-dead liver is increased. In 2006, our research group found functional and morphological injury in the livers of brain-dead donors, and we believe that protein kinase C-α (PKC-α) participates in this injury mechanism [34].

Changes in Liver Functions

The influence of brain death on liver function is controversial. Van der Hoeven et al. [1] first reported in 2000 that brain-dead donor livers are affected by hemodynamic stability and proved that organs have time-dependent progressive dysfunction (gradual increase of lactate dehydrogenase (LDH), creatinine, aspartate aminotransferase (AST), α-glutathione-S-transferase (α-GST), and no significant changes in alanine aminotransferase (ALT)) before organ procurement and preservation. This report was similar to their report published in 2001, which found no clear reason for the increase, but implied the damage to the hepatocytes as a potential candidate. The study by Compagnon et al. [35], published in 2002, observed that there are no significant changes in AST, ALT, LDH, gamma-glutamyl transpeptidase (GGT), and T.Bil (except for alkline phosphatase (AKP)) before organ removal in brain-dead donors compared with those that have been brain dead for 16 h. After orthotopic transplantation of donor livers cold-preserved for 24 h in the University of Wisconsin solution, there were no significant differences in AST, ALT, and LDH in two groups, which gradually became normal after 2-3 days. Golling et al. [36] reported in 2003 that aspartate aminotransferase/glutamate-oxaloacetate transaminase (AST/GOT) of hypotensive and normotensive brain-dead pigs both increased after induction of brain death. Olinga et al. [18] showed there were no differences in the levels of ATP between brain-dead rat livers and liver from live rats; furthermore, brain death within 6 h does not influence the viability of the donor liver. This report contrasts the findings of Novitzky et al. [37], which showed that brain death induces anaerobic metabolism, increases of serum lactate, and decreases ATP levels. This might be related to blood pressure during brain death. Novitzky et al kept low blood pressure in the whole experiment. Serum lactate does not increase when the blood pressure was kept normal, which shows that anaerobic metabolism is not caused by brain death but is instead related to the hypotension induced by brain death. In 2007, Weiss reported that levels of ALT and AST in the livers of brain-dead donors were significantly higher in the first and third days after transplantation compared with those of living donors [19]. Total bilirubin increased significantly in the tenth day after transplantation. Our group reported that ALT and AST levels kept increasing with time and were higher than those from non-brain-dead donors [38]. However, the exact mechanism by which brain death affects liver function remains unexplained.

The Influence of Brain Death on the Outcomes of Transplantation

In a study comparing the survival of rats that received liver transplants from brain-dead donors versus transplants from non-brain-dead donors, Van der Hoeven et al. [29] found that the recipient survival with immediately transplanted livers or those stored for 20 h was 100% when the livers came from non-brain-dead donors. However, survival decreases when the livers were procured from brain-dead donors. Survival was 75% when storage time was 0 h and 20% when the livers were cold stored for 20 h before transplantation. Due to an unclear mechanism, organs from brain-dead donors are more sensitive to cold preservation. In 2003, the author integrated the reports of Kusaka et al. [39] and Pratchke et al. [40] and considered that brain death will surely decrease the viability of transplanted livers and kidneys in animal models. The decrease in organ function is associated with donor organ inflammation induced by the release of cytokines and chemokines before procurement of brain-dead organs [13]. Compagnon et al. [35] showed that the effects of brain death on liver graft are hard to ascertain. Most research has been established based on rodent brain-dead models. No evidence supporting the detrimental effect of brain death on liver allografts have been reported in large animal models or in clinical studies. The author established the models of orthotopic liver transplantation (OLT) using non-brain-dead donors as controls and found that the animals in both groups were healthy, with a 100% survival rate, without pre- or postoperative immunosuppression at day 7 after operation. The study showed that brain death does not significantly influence donor livers before removal. Donor brain death and prolonged liver graft preservation does not interact significantly to impair liver function and survival after transplantation. This result was different from the report by Van der Hoeven et al. in 2001 [29]. In China, Wu et al. reported that the short-term outcomes of recipients of liver grafts from brain-dead donors are similar to those of recipients of grafts from non-heart-beating donors (among which nine cases received livers from brain-dead donor), indicating the safe clinical use of liver grafts from brain-dead donors [41]. In the Netherlands in 2001-2006, all adult recipients of full-size OLT from donors after cardiac death (DCD, n = 55) and donors after brain death (DBD, n = 471) were analyzed and found that OLT using controlled DCD grafts and restrictive criteria results in patient and graft survival rates similar to those of DBD OLT despite a higher risk of biliary stricture [42].

Therefore, results of the reports on present experimental and clinical research in combination with our own experiment have shown that brain death causes a certain decrease in the quality of donor livers, although controversy still exists. Aside from brain death–mediated immune activation, unstable hemodynamics, hypoxemia, and catecholamines affect the quality of donor livers. In addition, many experimental brain-dead models show the coexistence of organ dysfunction and inflammation caused by a fatal central lesion. The process of brain death is associated with the release and expressions of cytokines in the graft [29,39,40]. There are indeed significant differences in the immune states between living donors and brain-dead donors [43]. Many studies have described the interaction between cytokines, endothelial antigens, and the succedent adhesion molecules in donor organs and the importance of immune activation [43,44,45]. Immunohistochemical staining showed CD3+ lymphocyte and macrophage infiltration are increased in brain-dead donor liver tissues [13,46], which was caused mainly by cytokine-induced cell adhesion molecules, such as ICAM-1, which in turn induces the expression of inflammatory cytokines IL-1, IL-6, IFN-γ, and TNF-α [13,29,47]. The peak time of cytokine expressions and cell infiltration were during brain death and organ procurement but not after reperfusion. Furthermore, the appearance of activated CD25+ cells in brain-dead donor liver tissues before procurement explained partly the increased number of primary nonfunction after transplantation of organs from deceased donors. In living donors, surgical manipulation, perfusion and other injuries lead to a slow and moderate step by step activation, which however, never reached the intensity of immune activation observed in brain dead donors. The expression of the protective gene HO-1 also increases during the procurement of organs from brain-dead donor, but HO-1 is highly sensitive to ischemia, hypotension, or reperfusion, which causes oxidative stress [48-51]. Therefore, we ask whether the effects of brain death on donors would affect the survival rate of liver grafts and whether it is reversible. We also aim to determine if there are possible interventions to manage or possibly eliminate the adverse effects of brain death and improve the quality of donor organs, reduce the incidence of postoperative complications, and increase the survival rate of patients. These remain controversial because there are no further clinical studies, especially those involving large animals.

Exploration of the protection of the brain-dead liver

Brain death is not a fixed and static condition, but a dynamic process that directly affects the quality of donor organs. The progressive dysfunction of the liver is closely related with the inflammation caused by the release of cytokines and chemokines during brain death. The hours between the declaration of brain death and organ retrieval might provide an opportunity for cytoprotective intervention and, thus, counteract or potentially diminish the detrimental effects of brain death. This could further improve donor organ quality, resulting in fewer complications, increased survival, and, most importantly, better long-term function of the cadaveric donor organ.

Prastschke et al. reported in 2005 [17] and in 2008 [51] that steroids, such as methylprednisolone, decreases immune activation. In a prospective, randomized study, they found that steroid decreases the expression of cytokines in serum and organs, thereby improving organ function after liver transplantation and alleviating reperfusion injury. In their follow-up study, they found that the incidence of acute rejection decreases with steroid administration. Steroid intervention in brain-dead donors can lessen cytokine activation to levels as low as those in living organ transplantation. Therefore, we suggest that all brain-dead donors be administered with steroids after brain death. Dopamine can stimulate and induce protective enzymes like HO-1, which provide organs with a higher ability to resist reperfusion injury [52]; this compound should be continuously used during the procurement. In addition, catecholamines can protect endotheliocytes from cold injury through the clearance of reactive oxygen species (ROS) [53]. Since 1987, when Weinberg et al. found for the first time that glycine protects isolated organs, more attention has been paid to its mechanism of action and its protection of grafts from livers, kidneys, lungs, and so on. In 2004, we established brain-dead donor OLT models with Wistar rats using glycine and glycine with strychnine treatments [54]. By analyzing the blood samples taken before the cold douche of donor livers and at 2 and 6 h after restoration blood flow into the hepatic portal veins after transplantation, we found that the levels of AST, ALT, TNF-α, and HA in the glycine group were lower than those in the control group. Electron microscopy of liver morphology, revealed Kupffer cells activation, expansion of rough endoplasmic reticulum, appearance of primary and secondary lysosomes in the cytoplasm, liver cell swelling, vacuolar degeneration, cisternal expansion of endoplasmic reticulum, mitochondrial swelling, nuclear chromosome margination and cell apoptosis in the liver of donors not treated with glycine. In the glycine group, hepatocytes were less damaged and Kupffer cell activation was not significant. This research showed that glycine provides protection for brain-dead donor livers. This protection seems to be mediated by the suppression of activation of Kupffer cells. The studies by Wheeler et al. [55] and Schemmer et al. [56] on the mechanism of glycine in Kupffer cells showed that it activates glycine-dependent chloride channels on the Kupffer cells (which is called glycine receptors). This induces the internal flow of chloride ions, cell membrane hyperpolarization, and suppression of the opening of voltage-dependent calcium channels, which suppress the activation of Kupffer cells and the release of cytokines. This finding is similar to the protection provided by N-acetylcysteine [57] and breviscapine [34] to livers in our previous reports.

These investigations reveal the mechanism in which liver injury occurs during brain death and discusses the possible interventions that can improve the viability of brain-dead donor liver transplants. The discovery of the cysteine protease family (also called caspases) led to the realization that apoptosis is caused by the activation of the fibrinolytic system through caspases activated by a special death signal. Caspases are the core of cell apoptosis. To induce or suppress cell apoptosis through the activation or suppression of the caspase system has become a new concept for the treatment of apoptosis-related diseases. The protection provided by caspase inhibitors for brain-dead donor livers still needs experimental verification. Furthermore, the suppression of apoptosis by the overexpression of target genes such as BCL-2, A20, and so on through gene transfection is worth exploring.

However, the mechanism of the adverse effects of brain death on potential donor organs still cannot be clearly explained. Methods for protecting donors more effectively still need further exploration, which is our next research target.

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