Targeting brain death-induced injury
van Erp, Anne Cornelie
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Introduction
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Organ transplantation remains the preferred life-saving treatment for most patients withORGAN DONATION, PRESERVATION AND TRANSPLANTATION
end-stage liver and kidney disease, as it can improve patients’ quality of life as well as their survival rates1-3. Unfortunately, not every patient on the waiting list can receive an
organ because of a global shortage of suitable organ grafts. As a result, 12 people die each day while waiting for an organ transplant in Europe alone4,5. This problem underlines the
need for a concerted action within the transplant community to increase the number of available organs. This pertains mostly to organs obtained from deceased donors to avoid ethical problems related to living organ donation as well as illegal organ trafficking. On an international level, this effort has resulted in the establishment of organizations such as the Eurotransplant International Foundation, a non-profit organization established to optimize the allocation and distribution of organs amongst a number of European countries5. On
a national level, several countries including The Netherlands have adopted legislation that automatically enters their civilians as potential organ donors unless they personally object. Another approach to increase the donor pool is to increase the use of organs of suboptimal quality. However, this approach mandates an improvement of organ quality prior to transplantation in order not to risk poor transplantation outcomes. As the quality of the organ graft may be challenged during each step of the transplantation process, this approach should encompass strategies and treatments in the donor, but also afterwards during organ preservation and in the recipient. To facilitate organ-improving strategies, the first step is to understand which injuries the graft endures during the transplantation process.
ORGAN DONATION
Both chronic (aging, pre-existing medical conditions) and acute injuries (donor death, organ retrieval strategies) in the donor are risk factors for impaired graft survival after transplantation6. Of these injuries, donor age is considered a classical risk factor that is
associated with both short-term and long-term graft survival7,8. However, recent studies
suggest that biological organ age and not donor age is a better predictor of transplantation outcomes9-11. Halloran et al. postulated that the accumulation of aging combined with
exposure to injury and stressors impairs the ability of an organ to repair and remodel, thereby hindering graft survival6. This might explain why we observe a clear difference
in survival dependent on the type of organ donor used. Of all donor types, organ grafts obtained from living donors are superior when compared to those obtained from deceased donors. However, the number of living organ grafts is limited, which means that the majority of organs used are obtained from decreased donors. Deceased donors can be classified into deceased brain-dead (DBD) donors or deceased cardiac death (DCD) donors. Of the two, most organs worldwide are obtained from DBD donors. Nevertheless, the number of DCD
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organs continues to increase, particularly since more countries are accepting organs from these donors12. In addition, many countries have started using suboptimal organs obtained
from so-called extended criteria donors (ECD)13. ECD are over 60 years of age, or between
50-60 years with comorbidities including hypertension, impaired estimated GFR based on plasma creatinine (> 1.5 mg/dL), age, and gender, or death by a cerebrovascular incident. When compared to living donation, deceased donation is associated with allograft dysfunction or delayed graft function, impaired survival or even higher mortality rates following transplantation14-16. This inferiority of deceased donors is caused by pathophysiological
changes of death. In DBD donors, most commonly cerebrovascular incidents or traumatic brain injuries cause increased intracranial pressure. When the body fails to maintain cerebral perfusion, this results in ischemia of the brain, and brain stem. As a result, large amounts of catecholamines are released and a cascade of derailments commences that includes inflammation, hemodynamic instability, and hormonal and metabolic changes17-19. In DCD
donors, not a cerebral event but cardiopulmonary arrest causes hypoxia, which poses a great ischemic insult to the organs. The subsequent prolonged period of warm ischemia adds additional ischemic damage to the organs and is considered another risk factor associated with impaired graft function and higher mortality rates following transplantation20,21.
Altogether, this suggests that minimizing and targeting the accumulation of injuries in the donor could reduce cellular injury. This strategy could improve graft function and survival after transplantation and even allow more organs to be suitable for transplantation.
Organ preservation
Following this period of donor-related injuries, organ grafts suffer additional injury during the preservation period. For decades, organs have been statically preserved on ice. This strategy was based on the rate-of-life theory, which states that aging and longevity are regulated by the rate of cellular metabolism22. According to this principle, hypothermic preservation
intends to lower the metabolic rate, thereby reducing hypoxic injury and preserving cellular function23. To ensure tolerance of organs to hypothermia, preservation solutions have been
developed to counter negative side effects of hypothermic preservation including edema, accumulation of reactive oxygen species (ROS) production, ATP depletion, mitochondrial damage, a switch to anaerobic glycolytic metabolism, and microvascular changes23-25. With
this in mind, prolonged duration of the cold ischemia is considered an independent risk factor for a nonfunctioning or dysfunctioning transplant, particularly in marginal or high-risk donors26,27.
These negative side effects of cold storage have recently led to the first clinical implementation of hypothermic machine perfusion (HMP). This technique allows continuous, pulsatile perfusion of the organ at 4 to 10°C, while blood and other components are flushed out
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and the organ equilibrates with the perfusion solution23. HMP has clear benefits over static
cold storage in kidney transplantation, evidenced by improved graft function and survival rates23,28. Despite these benefits, HMP has only recently begun to be clinically implemented
in the field of kidney, liver, heart, and lung transplantation. Static cold storage currently remains the only clinical preservation method of the pancreas26. Adaptations of HMP that are
currently being investigated pre-clinically are the addition of oxygen and other additives to the perfusion fluid, as well as perfusion at subnormothermic (25°C) or normothermic (37°C) temperatures. Especially normothermic temperatures would add the additional benefit of allowing viability testing of organs prior to transplantation. The key to all these preservation methods is the improvement of graft quality by limiting (the duration of) ischemic injury, preventing abrupt reperfusion and preserving or restoring cellular energy supplies.
Organ transplantation
Optimizing graft quality prior to transplantation is especially important given that the reintroduction of warm oxygenated blood in the recipient will only amplify injury to the organ graft. After a period of cold ischemia, graft reperfusion causes immediate ROS production by the vascular cells of the donor allograft, followed by a subsequent hit of ROS production originating from the recipient’s phagocytes29. Interestingly, the initial ROS produced by the
donor’s vascular cells trigger the subsequent second burst of ROS, together reducing the capacity of the anti-oxidant machinery. Hence, this phenomenon has been described as a vicious cycle with excess ROS production as its end result29. One of the main contributors
to this cycle are the mitochondria, which are known to increase their ROS production in response to hypoxia30. This ROS production in turn facilitates the initiation of various cellular
death pathways, including necrosis, apoptosis, and autophagy24,31,32. It is suggested that the
amount and duration of the oxidative injury related to first ischemia and then reperfusion, so-called ischemia-reperfusion injury (IRI), is responsible for the ischemic damage and immune activation immediately after transplantation. This makes oxidative stress an important factor which can ultimately result in rejection of the organ graft24. Furthermore,
the level of IRI subsequently determines the extent to which cellular death pathways such as autophagy and apoptosis become activated. Their level of activation and interplay seems to determine whether the end result is pro-survival or pro-death33,34.
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TARGETING BRAIN DEATH-INDUCED INJURY
The potential benefit for patients with organ failure together with the global organ shortage is the driving force behind the body of research that has tried to elucidate what damages the graft during each step of the transplantation process. Recently, this has led to the clinical implementation of ex vivo hypothermic kidney perfusion as the preferred preservation method. However, the great potential of targeted treatments during ex vivo organ perfusion and the sometimes ethical difficulty of treating deceased donors, should not be a reason to refrain from investigating or targeting organ grafts in deceased donors. Even though each step of the transplantation process may harm the organ graft, a very substantial amount of damage already occurs within the deceased organ donor. Given that many intracellular pathways such as oxidative stress and autophagy (introduced in more detail later) can be either detrimental or beneficial depending on the level of injury or stress, particularly early treatment of donor-related injuries could be of great benefit. Besides expanding on the current knowledge on donor pathophysiology, research should investigate novel injury mechanisms in the brain-dead donor, such as metabolic changes and autophagy dysregulation. Understanding what damages the organ prior to transplantation is essential to optimize organ-specific treatments in the donor but also during later stages of the transplantation process. Finally, if the outcome of a transplantation can already be predicted in the donor or during organ preservation, this would greatly benefit the success of transplantations while minimizing the impact on recipients.
Brain death physiology
Most organs world-wide are obtained from DBD donors12. Brain death is defined as a state with irreversible absence of brain and brainstem function, in which mechanical ventilation is required to prevent apneas while the systemic circulation remains intact35. Several common etiologies of brain death include cerebrovascular accidents, traumatic brain injury, and diffuse hypoxia. The common denominator in each of these injuries is a rise in intracranial pressure. When the risen cerebral pressure cannot be overcome by a rise in blood pressure, this results in hypoperfusion of the brain and subsequent progressive ischemia of the brain, brainstem, and ultimately spinal cord. Herniation of the ischemic brain stem results in sympathetic hyperactivity that is characterized by an immediate increase in systemic blood pressure and peripheral vasoconstriction due to the release of endogenous catecholamines, also called the catecholamine storm17,36. This catecholamine storm has been described as the body’s final attempt to overcome the rise in intracranial pressure. This vasoconstrictive response results in decreased blood flow through peripheral organs such as the liver and kidneys37. The systemic hypertension also stimulates (to a lesser extent) parasympathetic activity via the baroreceptors, resulting in subsequent bradycardia. These changes, together called the Cushing response, are characteristic for the brain death condition.
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This hypertensive period is followed by a decline in sympathetic tone, which marks the beginning of the hemodynamic instability in the DBD donor35. In addition to these changes in hemodynamics, ischemia of the brain results in failure of the hypothalamus and pituitary axis. As a consequence, a depletion of antidiuretic hormone is evident in the majority of the brain-dead donors38. The resulting diabetes insipidus causes increased diuresis and risk of hypovolemia and further contributes to the hemodynamically unstable condition. In addition, plasma levels of free thyroid hormone, thyroid stimulating hormone, and cortisol generally decline39,40. Besides hemodynamic and hormonal changes, BD is characterized as a systemic inflammatory state, seen by a rise in circulating cytokines, including interleukin (IL)-6, IL-10, MCP-1, and TNF-α41-44.This systemic inflammatory environment triggers a local response in the kidneys, liver, and lungs. The inflammatory and apoptotic response in these organs is the results of activation of the vascular endothelium, the complement and coagulation system, as well as the innate and adaptive immune response45. What triggers this pro-inflammatory environment during brain death is not well understood. Nevertheless, cerebral cytokines from the dying cerebrum46, complement activation47, translocation of bacteria from the intestines48, and organ-specific inflammation49 have all been implicated. Altogether, brain death-induced pathophysiology negatively affects organ quality prior to transplantation and predisposes the recipients of these grafts to a higher risk of acute rejection, delayed graft function and lower survival rates after transplantation16,42,50. Targeting brain death-induced injury is, therefore, essential.
AIM OF THIS THESIS
The aim of this thesis is to review and expand on the current knowledge required to target brain death-induced injury (see Fig 1). The first part of the thesis (Chapters 1 – 4) focuses on interventions in the donor that target brain death-induced pathophysiological changes. The second part of this thesis (Chapters 5 – 8) expands on this knowledge by investigating novel injury mechanisms pertaining metabolic changes and autophagy (dys)regulation during brain death.
Interventions in the brain-dead donor
Currently, brain-dead donor management protocols are aimed at targeting brain death-related pathophysiological changes. Despite considerable differences per individual center, protocols have focused mainly on providing hemodynamic support, suppressing the immune system, optimizing donor ventilation management, controlling donor body temperature, and administrating hormone replacement therapy51. Providing hemodynamic
support and optimizing organ oxygenation is important, given the hemodynamic instability that is evident within the brain-dead donor. Immunosuppressive therapy to counteract brain death-induced inflammation is also clinically relevant, as donor plasma levels of pro-inflammatory cytokine IL-6 were inversely correlated to recipient six-month
hospital-1
free survival54 and an increased risk of recipient death following lung transplantation52-54.
However, despite promising animal studies56,57, immunosuppressive therapy in brain-dead
donors has not been able to improve the outcomes of liver and kidney transplantations58-61
(see Fig 2). Finally, despite mixed reports about the effectiveness of thyroid hormone replacement therapies, its use has increased over the years40,62-64. Altogether, this highlights
that despite the extensive body of preclinical and clinical research on interventions in the brain-dead donor, we are still lacking a universally accepted, optimized brain-dead donor management protocol.
Figure 1. Targeting brain death-induced injury. Brain death results in hormonal changes, hemodynamic
instability, inflammation, and oxidative stress. It is unclear how these changes affect organ-specific metabolism, perfusion, mitochondrial function, and autophagy. Together these changes negatively affect organ quality, which impacts transplantation outcomes and patient and graft survival. Targeting brain death-induced injury is essential to optimize organ quality prior to transplantation, particularly given the subsequent injuries the graft endures during organ preservation and transplantation, as well as the global organ shortage.
As a starting point for this thesis in Chapter 2, we provided an update on all systematically tested, clinical interventions that have been tested in brain-dead organ donors thus far (see Fig 2). Only those studies were included that focused on the effects on organ quality and graft and/or patient survival after transplantation. In Chapter 3, we tested whether EA230, an oligopeptide of human chorionic gonadotropin with promising anti-inflammatory properties in models of septic and haemorrhage shock, would attenuate brain death-induced inflammation. Finally, in Chapter 4, we studied whether pre-conditioning of brain-dead animals with free thyroid hormone T3 could improve liver function and reduce apoptosic cell death.
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Figure 2. Overview of all systematically tested, clinical treatments or interventions in the brain-dead donor
with outcome parameters pertaining the lungs, liver, heart, and kidneys. Treatments or interventions denoted in black did not affect graft function or graft and patient survival. Treatments or interventions denoted in green were beneficial, those in red were detrimental, and those in orange showed mixed results.
NOVEL INJURY MECHANISMS
Previous studies have indicated that brain death alters the plasma metabolite profile and shifts the balance from aerobic to anaerobic metabolism65. To explain these metabolic
changes, several theories have been provided. Firstly, these changes have been attributed to mitochondrial impairment, as this was previously observed in the muscles of brain-dead patients66 and the hearts of brain-dead pigs67. Alternatively, the hemodynamic instability
and initial organ hypoperfusion immediately following the catecholamine storm have been implicated as the underlying cause. Regardless, the metabolic status of organs prior to
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transplantation is of clinical importance, as these changes have been linked to transplantation outcomes following both kidney68,69 and liver transplantation70,71. However, effects of donor
brain death on metabolism in the individual organs has not previously been investigated. Therefore, in Chapter 5, we investigated how brain death affects metabolism, both systemically as well as in the liver and kidney. Besides studying major metabolic pathways, we investigated whether mitochondrial function and organ perfusion were altered during brain death. In Chapter 6, we used a non-invasive imaging tool to study in vivo, metabolic pathways in the liver and kidney during and following brain death. Using hyperpolarized magnetic resonance imaging with MRI-active pyruvate molecules, we were able to visualize metabolic pathways in real time during brain death. Afterwards, we visualized glucose metabolism during ex vivo organ reperfusion using radioactively labelled glucose.
Oxidative stress, hemodynamic instability, inflammation, and hormonal perturbances induced during brain death are each influencers of autophagy72-74. Autophagy is an intracellular
degradation pathway that removes, degrades, and recycles cellular constituents75. Autophagy
normally occurs at a basal level within the cells and serves as a cellular housekeeper that removes damaged or unwanted organelles or cellular constituents73,75. Several types
of autophagy exist, but all types of autophagy involve the transportation of intracellular compounds to the lysosomes for degradation. In the presence of cellular stressors such as hypoxia, inflammation, or energy depletion, autophagy becomes stimulated and protects the cell by removing damaged or toxic cellular products76,77. In this way, autophagy is
generally considered to be a protective, stress-adaptation pathway that can counter cellular death pathways such as apoptosis77,78. Conversely, excessive autophagy stimulation can be
detrimental and can push the balance away from a protective towards a detrimental role for autophagy, as is seen in disease states such as cancer, neurodegeneration, aging, and IRI79,80.
This is of particular importance, given the current increased use of older and extended criteria donors. Even though autophagy has been implicated to play a role during oxidative stress and IRI, the exact role that autophagy plays during the transplantation process is only beginning to be understood81. In Chapter 7, we reviewed all the available knowledge on
the role that autophagy and oxidative stress play during each step of the transplantation process. Furthermore, we covered the complex interdependency of these two pathways and discussed several compounds that target each of these pathways. Finally, in Chapter
8 we investigated how brain death affects autophagy in the liver and kidney. Furthermore,
we studied whether stimulation of autophagy with mTOR-inhibitor rapamycin affected autophagy, organ quality, and apoptosis.
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