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REVIEW
Renal Warm Ischemia in Organ Donors After Circulatory Death

Chronic kidney disease is the most common type of organ failure worldwide, with a prevalence of 13.4% for all stages. Organ transplant is the only curative option for end-stage kidney failure. However, the shortage of organ donors remains a major obstacle in organ transplant, with donation after circulatory death being the most viable path to increasing the donor pool. The circumstances that surround this type of donation are different from donation after brain death, namely concerning warm ischemia times, which are longer and may preclude a successful transplant. This article describes the pathophysiology of warm ischemia and summarizes recent developments in technological and methodological practices that mitigate the mechanisms of warm ischemia. Anoxia, mitochondrial dysfunction, calcium overload, oxidative and nitrosative stress, immune response, and no reflow are the main mechanisms by which ischemia leads to cell death and organ dysfunction. In situ oxygenated recirculation, abdominal normothermic organ recirculation, abdominal hypothermic organ recirculation, and ex vivo machine perfusion ensure continued organ perfusion and prevent prolonged warm ischemia in organ donation. These practices, coupled with optimizations in the identification and assessment of potential donors after circulatory death, may lead to a significant increase in the number and success rates of organ transplant worldwide.


Key words : Cellular mechanisms, Donation after circulatory death, Extracorporeal membrane oxygenation, Organ transplantation, Renal transplantation

Introduction

Chronic kidney disease is the most common type of organ failure worldwide, with a prevalence of 13.4% for all stages of chronic kidney disease and 0.1% for end-stage disease. It represents a global health burden with a high economic cost to health care systems worldwide: according to a Swedish study, among patients with stage 4 or 5 chronic kidney disease, those who are receiving hemodialysis have the highest annual cost (€86 000) whereas transplant recipients have the lowest (€15 500).1 Chronic kidney disease is also an independent risk factor for cardiovascular disease: all stages are associated with increased risks of cardiovascular morbidity and mortality and decreased quality of life.2

Organ transplant is currently the only curative option for end-stage kidney failure, with lower cardiovascular mortality and event rates and least economic burden compared with all forms of dialysis.3 However, the gap between the number of performed transplants worldwide and the number of patients on wait lists is still substantial: as of 2016, only 62 333 of the 279 910 patients (22.27%) on wait lists received a kidney transplant.4 This leaves an enormous portion of patients dependent on dialysis, some of which will die from complications of the disease and inefficiency of the treatment of cardiovascular disease, which is the major cause of death in patients with end-stage kidney disease.

Increasing the number of donors after circulatory death (DCD) is the most viable way of expanding the organ donor pool.5 Many countries have already made legal and social efforts to include DCD under controlled, uncontrolled, or both settings, with positive results. In the Netherlands, from 2000 to 2009, DCD contributed from 22% to 50% of all deceased organ donors; in the United Kingdom, over the same period, DCD composed 34% of all deceased donors. Utilization rates in these countries were 90% and 93%, respectively.6

With such a fast inclusion of DCD across diverse regions, attention must be drawn into understanding the particular conditions of death and organ ischemia surrounding these donors and their effects on organ function. Such circumstances are different from those in donors after brain death (DBD); therefore, the approach to these 2 must be distinct to increase the odds of a successful transplant and to decrease long-term complications for organ recipients. To achieve this goal, clinicians must be familiar with the cellular and subcellular echanisms of ischemia, their interactions, and their overall contribution to the observed kidney injury.

Considering the high potential of injury in kidneys from DCD due to increased warm and cold ischemic times, preventive approaches must be undertaken to mitigate ischemic injury, in which ischemia-enhancing mechanisms are tackled either individually or as a group, through mechanical, pharmacological, and genetic approaches.

In this review, we provide insight into the cellular and subcellular mechanisms of warm ischemic injury in kidney transplants from DCD (anoxia, calcium overload, mitochondrial dysfunction, oxidative and nitrosative stress, immune response, and no reflow). Special focus will be devoted to the existing preventive and mitigating approaches, mainly interventions that have already undergone clinical trials.

Methods
Eligible studies and articles were identified by an electronic search of PubMed and Scopus involving studies published from 1965 and 2019. The sensitive search strategy combined the following key words: warm ischemia, ischemic injury, kidney injury, reperfusion injury, hypoxia, kidney transplant, non-heart beating, donation after cardiac death, donation after circulatory death, donation after brain death, and organ preservation. All articles and cross-referenced studies from retrieved articles were screened for pertinent information and reviewed by all authors.

Inclusion criteria consisted of experimental and review articles, systematic or not, published as original studies with available abstracts. Publications not written in English were excluded.

Specific Conditions in Donation After Circulatory Death
Although, in the inceptive development of organ transplantation, the first donors were DCD, DBD has been, since the Harvard Medical School pivotal report defining brain death,7 the predominant form of donation in many countries.4 This can be explained by the fact that medical management of DBD ensures organ viability for a far longer period of time and in a much more uneventful manner than in the settings of DCD (mainly uncontrolled DCD). In other words, although a timeline exists, there is no immediate danger to organ viability in DBD. Between the diagnosis of brain death and organ retrieval, consent can be obtained from the family (if presumed consent is absent), all concerned entities can be notified, and organs can be procured over a variable period of time after the diagnosis.

Despite DBD having more ideal conditions with regard to organ ischemia time and overall feasibility of the procurement procedures, both patient and graft survival and mid-term and long-term outcomes are similar in kidneys transplanted from DBD versus DCD.8 Moreover, despite higher rates of delayed graft function (DGF) and acute rejection in kidney transplants involving DCD, subsequent outcomes of kidney transplant in DCD with DGF are better than in DBD with DGF, with outcomes similar to DCD without DGF.9 Primary nonfunction (PNF) is extremely low in DCD, even within extended-criteria donors.10 An exaggerated focus on short-term outcomes, namely DGF, leads to the potential neglect of this group of donors.

In the context of DCD, overall ischemia times are longer yet variable. Nonetheless, in uncontrolled DCD (DCD categorized with Maastricht Classification I and II; Table 1),11 resuscitation efforts ensure a low-flow environment that prevents full-on ischemia, although with intermittent periods of no flow. Despite this, uncontrolled DCD often spend a significant amount of time in no-flow or low-flow environments until organ retrieval occurs or the donor is cannulated for extracorporeal circulation. In one Portuguese center, a maximum of 150 minutes is allowed from cardiac arrest to organ preservation, in this case through abdominal normothermic oxygenated recirculation (ANOR).12 In these settings, this period of time corresponds to the warm ischemia time.

In regard to controlled DCD (DCD categorized with Maastricht Classification III and IV),11 duration of warm ischemia is usually shorter yet variable. In these settings, the sum of the agonal phase (defined as the time from withdrawal of life-sustaining treatment [WLST] to cardiac arrest), the 10 minute no-touch period, and the time to organ preservation make up the warm ischemia time. The equivalence between warm ischemia time and the sum of these periods is debatable because the agonal phase comprises an initial time of normal cardiovascular and respiratory function that ensures normal blood flow and organ oxygenation. In all institutions in the Netherlands, maximum agonal phase duration according to the organ retrieved is as follows: < 60 minutes for liver, lung, and pancreas donation and
< 120 minutes for kidney donation.13

Metabolic Adaptation to Anoxia
The onset of hypoxia as a result of the decrease in blood flow is the main driver of extracellular, cellular, and subcellular changes that occur during warm ischemia. Within the first few minutes of ischemia, absence of oxygen and changes in cellular oxidation-reduction states induce the activation of anaerobic glycolytic metabolic pathways as alternative ATP sources. However, this results in the production of only a fraction of the ATP produced under aerobic conditions, which is insufficient to meet cellular demands.14

Concomitantly with the activation of glycolytic pathways and the exhaustion of substrate reservoirs, toxic metabolic products start to accumulate, namely, inorganic phosphate, protons, creatine, glycolysis products, H+, lactates, and nicotinamide adenine dinucleotide (NADH). The accumulation of these products can cause both toxic and osmolar damage to the cells, eventually resulting in cell death.15

Ultimately, the glycolytic pathway is fully inhibited by the sum of mainly 3 factors. First is the accumulation of H+, lactates, and NADH that inhibits glyceraldehyde phosphate dehydrogenase, thus stopping the glycolytic pathway. The second is the exhaustion of cellular glycogen reservoirs. Finally, and most importantly, is ATP exhaustion, which prevents the phosphorylation of fructose-6-phosphate.15 This combination, coupled with the inhibition of other energy substrates and pathways, such as phosphocreatine, leads to the full arrest of ATP production.

Although variable in humans, attempts have been made to clarify the amount of warm ischemia time that results in irreversible damage to the tissue. In a rabbit kidney model, should the ischemia time last longer than 24 hours, ATP synthase activity is irreversibly lost and definite cell death ensues.16

Calcium Overload
Mitochondrial dysfunction is one of the main drivers of cell death, either by apoptosis or necrosis, especially during reperfusion injury. A great contributor to this dysfunction is calcium accumulation within the cell and within the mitochondria itself, especially on reperfusion, where restoration of circulation delivers calcium to the cell in a rapid and sudden fashion. Calcium overload occurs mainly by 3 different pathways (Figure 1).

In the first pathway, which occurs during ischemia and due to ATP exhaustion, Na/K-ATPases stop pumping Na+ out of the cell. This accumulation of Na+ leads to severe changes in membrane potential, which would result in rapid cell death. Therefore, extrusion of Na+ becomes paramount. One of the transporters used for this purpose is the membrane Na+/Ca2+ antiporter, which normally expels Ca2+ out of the cell. By reversing its direction, this antiporter removes 2 atoms of Na+ in exchange for 1 atom of Ca2+, leading to intracellular calcium accumulation.17

In the second pathway, which occurs during ischemia, the activation of the glycolytic pathway leads to the accumulation of lactate, protons, and NAD+, causing a sudden and severe drop in cellular pH. To counteract this drop, the membrane Na+/H+ exchanger is activated, leading to an intracellular accumulation of Na+. As discussed above, the cell cannot sustain this accumulation of Na+ and the mechanism of calcium overload is the same as described above.18

In the third pathway, which is due to the overall metabolic changes within the cell, Ca2+ reuptake into the endoplasmic reticulum by the SERCA ATPase is impaired, whereas Ca2+ release through the ryanodine receptor is fully enhanced. Although not as substantially important as the aforementioned mechanisms, this also contributes to the intracellular calcium overload observed in warm ischemic injury.19

To maintain mitochondrial membrane potential in the face of calcium overload, transport and retention of calcium within the mitochondria are necessary. This calcium accumulation in the mitochondria causes inhibition of complex I and later of complexes III and IV and, more importantly, activation of the mitochondrial permeability transition (MPT), a nonselective pore in the inner mitochondrial membrane that is activated in certain pathologic conditions such as ischemia.20 The MPT response is one of the main drivers of cell death during ischemia and will be discussed below.

Elevation of Ca2+ also causes the activation of normally inactive enzymes and proteases, such as calmodulin-dependent protein kinase and calpains, which destroy a variety of cell components (cytoskeleton, endoplasmic reticulum, and mito­chondrial proteins), therefore contributing to cell death.21

Mitochondrial Dysfunction
During ischemia, the lack of circulation prevents oxygen delivery to the organs. Because cells exhaust the remaining oxygen rapidly, electron flow through the respiratory chain is inhibited, leading to the arrest of ADP phosphorylation through ATP synthase. In an attempt to maintain membrane potential in the face of the inhibited electron transfer, ATP synthase actually starts acting in reverse, consuming the almost depleted ATP reservoirs of the cell.

As discussed before, due to calcium overload, among other factors, the MPT response is activated. This is a crucial step in the process by which ischemia leads to cell death. The mitochondrial permeability transition pore (MPTP) is a nonselective pore located in the inner membrane of the mitochondria that allows passage of molecules under 1500 Daltons in molecular weight.22 Because MPTP is inhibited by the low pH in the ischemic period, the MPT response is only activated on reperfusion, mostly due to the rapid increase in Ca2+ and in reactive oxygen species (ROS).23 The opening of the MPTP allows the passage of H+ ions into the matrix, which instantly leads to the irreversible loss of mitochondrial membrane potential, resulting in cell death in a rather rapid fashion.24

Oxidative and Nitrosative Stress
Although timely restoration of blood flow and organ reperfusion are the only ways to ensure cell survival after an ischemic event, reperfusion itself presents a threat to the cell in what is commonly called the “oxygen paradox.” Despite restoration of aerobic ATP production, reentry of oxygenated blood into the ischemic tissue results in the production of ROS, reactive nitrogen species, and reactive nitrogen oxide species (RNOS). Among other things, these molecules are responsible for damaging cell components, inducing cell death, stimulating the production of proinflammatory mediators, and facilitating leukocyte cell adhesive interactions.25

The traditional view of oxidative cell damage,
first described in 1985,26 defined it as an imbalance between pro- versus antioxidant compounds favoring the formation of pro-oxidant molecules that would directly lead to cell damage. Recently, 3 targets have been identified in oxidative stress: (1) direct molecule damage of all cell components (DNA, protein, lipids, and carbohydrates); (2) irreversible modification of key cell regulatory components through covalent, oxidative, and nitrosative changes27; and (3) the formation of nonradical oxidants such as hydrogen peroxide, which in turn mediate cell dysfunction through several mechanisms.28

Reactive oxygen species and reactive nitrogen oxide species
As discussed above, ROS are one of the major players in oxidative damage in ischemia-reperfusion injury. Within this category, superoxide anion radical (O2-) is the originally produced ROS and gives rise to all of the other ROS and RNOS that participate in oxidative stress injury.

Superoxide is mainly formed by enzymatic sources: xanthine oxidoreductase (XO), NADPH oxidase (NOX), cytochrome P450 oxidases, and nitric oxide synthase (NOS). The main source of superoxide varies across species, tissues, and even individuals. In kidney tissue, the mechanisms of oxidative damage in ischemia and reperfusion injury appear to be similar to those found in other human tissues, with particular emphasis on oxidation after ischemia and release of platelet activating factor and other lipids.29,30

In the kidney, endothelial cells are particularly rich in XO, which requires hypoxanthine and oxygen to fuel the production of superoxide. During ischemia, due to ATP depletion, and in reperfusion, due to the oxygen cell inflow, both hypoxanthine and oxygen suffer a sudden increase, leading to a burst in the production of superoxide. Inhibition of XO has been shown to reduce Ca2+ overload and markers of oxidant stress, illustrating the importance of this enzyme in the production of superoxide.31

With regard to NOX, 2 types of this enzyme have been shown to be involved in damaging superoxide production in the context of ischemia-reperfusion injury. The first one is the NOX present in phagocytic leukocytes responsible for the production of oxidative compounds that ensure a suitable host defense.32 In this scenario, superoxide is rapidly dismutated to hydrogen peroxide, which in turn originates hypochlorous acid. The second NOX is also present in vascular endothelial cells, although in a much lower concentration than in leukocytes. Whatever subtle effects endothelial NOX may have under normal conditions, in ischemia and mainly during reperfusion, both of these types of NOX contribute to the production of superoxide in a sufficient amount to cause oxidative stress and cellular damage.33

The cytochrome P450 enzymes are responsible for the univalent oxidation and reduction of xenobiotic compounds as well as other cellular molecules. Most of these enzymes are present in the liver, although a small amount can also be found in endothelial cells, including in the kidney. Although the precise role and importance of cytochrome P450 enzymes in ischemic injury are still unclear, they appear to contribute to cellular damage through the generation of ROS, dihydroxy decanoic acid, and, most importantly, 20-hydroxyeicosatetranoic acid. This potent vasoconstrictor has a yet unclear role in acute kidney injury, as its inhibition protects against damage in unilateral ischemic damage but enhances it in bilateral kidney injury.34-36

During the process of ATP production, over 90% of the oxygen that enters the cell is reduced to water by the respiratory chain, which is located inside the mitochondria. However, under normal conditions, 1% to 2% of the oxygen is reduced to superoxide in complex I and complex III enzymes, mainly due to “electron leak,” which is increased during reperfusion. This, coupled with the exhaustion of the cellular antioxidant capacities, inevitably leads to severe oxidative damage through an imbalance in pro- and antioxidant sources.37

The effects of the produced ROS and RNOS are varied and almost all contribute to cell damage and death, especially during the reperfusion phase of ischemia-reperfusion injury. As discussed, superoxide is the primary oxidant and all other RNOS eventually derive from it. We can separate superoxide effects into direct and indirect.

With regard to direct effects, superoxide can directly oxidize several enzymes such as aconitase, fumarase, NADH dehydrogenase, and creatine kinase.25 The inactivation of these enzymes would have catastrophic consequences to cell function. However, superoxide has a small lifetime because of its rapid spontaneous and catalytic (by superoxide dismutase) conversion to hydrogen peroxide, which prevents severe cell damage.

Indirect effects of superoxide arise from the products originated by its conversion. Hydroperoxyl radical is the conjugate acid of superoxide and originates through spontaneous conversion. Its production increases in low pH environments, such as in ischemia. Hydrogen peroxide, although the least reactive of all ROS, can directly act as a second messenger and modulate cell signaling. However, it can also give rise to the highly oxidative compound hydroxyl and can directly damage cell components that contain hemeproteins. Superoxide can give rise to the highly toxic proxynitrous acid through a reaction with nitric oxide and further protonation. All of these compounds have the potential to damage cell components through irreversible oxidation.

Immune Response in Ischemia
It is now well established, not only in the context of DCD but in all ischemic conditions, whether transient or permanent, that activation of the immune response contributes to further cell damage. However, this is still a matter of great debate, as conflicting reports of protective and damaging roles of the immune major players have been presented.38 In general, deposition of natural antibodies, complement activation, and neutrophil infiltration have been identified as the initiators of immune response in ischemia. Neutrophil and T-cell infiltration are the 2 most important cell types in ischemia-reperfusion injury and are described below.

Neutrophil infiltration
Neutrophil infiltration in an ischemia-reperfusion episode occurs as early as 30 minutes after reperfusion, and it can be seen in both animal and patient biopsies.39 This occurs as a result of a highly effective chemotactic gradient initiated by the release of several inflammatory messengers (tumor necrosis factor-α, interleukin 6, monocyte chemotactic protein 1, RANTES, macrophage inflammatory protein 2, among others) by the dendritic cells resident in the kidneys.40,41 This chemotactic gradient allows fast migration of neutrophils into the reperfused tissue, resulting in increased vascular permeability and cell damage. Of particular relevance are the molecules intercellular adhesion molecule 1 (ICAM-1), P-selectin, and interleukin 8, which potentiate neutrophil adhesion and infiltration (crucial for tissue damage) in a continuous fashion, maintaining a constant inflow of immune cells to the newly reperfused tissue.42

Upon arrival, neutrophils produce a large amount of ROS in the outer medulla (through its intracellular NADPH oxidase, which is activated when neutrophil adhesion takes place), proteinases, myeloperoxidase, and cationic peptides.41,43 The large amount of neutrophil affluence to the ischemic tissue, along with platelet and red blood cells, causes micro­vascular dysfunction upon reperfusion, leading to further tissue necrosis and exacerbated immune response, thereby contributing to the no-reflow phenomenon.39,44

T cells
The exact role of T cells and their direct effects on renal cells in ischemia-reperfusion injury are still mostly unclear, although recent animal and human models have shed light on the detrimental action of these cells, which exacerbate inflammatory injury in an acute ischemic event. Numerous experiments in animal models have proven that inhibition of T-cell function, either by blocking the stimulation process or by direct cell depletion, is beneficial in the context of an ischemic insult and mitigates cell damage and death.45-48 More specifically, after an ischemic event, transient T-cell depletion of CD4-positive T cells promoted renal protection, increased animal survival, and was associated with less acute tubular injury and earlier regeneration.49

Ischemia-reperfusion injury caused by T cells takes place not only after the release of alloantigens by the dying ischemic tissue (as previously thought) but also during the first critical phase after the cessation of blood flow. In this stage, activated T cells adhere to the endothelium of the capillary network, slow down the already diminished circulation, and reenter the systemic circulation shortly after, a phenomenon known as “hit-and-run.” Expression of ICAM-1, an adhesion molecule that facilitates leukocyte adhesion and infiltration, increases soon after an ischemic event, especially compared with that shown in acute toxic injury.50 As a result, the use of agents that prevent cell adhesion by blocking ICAM-1 mitigate ischemia-reperfusion damage, particularly in combination with lymphopenia-inducing drugs.51 Indeed, endothelial cells are the main drivers of T-cell activation in this context, having the ability to provide costimulatory signals to circulating cells (CD40, CD80, and CD86) and to act as antigen-presenting cells.52 This concept challenges the classical view of T-cell activation, taking place in a sterile environment and in the absence of an antigen stimulus, which has already been proven in a kidney model.45

No-Reflow Phenomenon
The no-reflow phenomenon in renal ischemia, first described in 1971,53 happens immediately after the reestablishment of blood flow in an ischemic event and consists of the failure of a large number of capillaries being reperfused. This phenomenon happens not only in the kidney but also in other major organs (brain, heart, small intestine, and skeletal muscle).

The initial hypothesis to explain this phenomenon proposed microvascular thrombosis as the pathologic mechanism behind the capillary obstruction. However, microvascular thrombus formation is rarely observed, and heparin treatment is not effective in restoring capillary perfusion after an ischemic event in skeletal muscle.54

Several items of indirect evidence have put leukocyte infiltration, namely neutrophils, at the center stage of the development of this phenomenon. It has been proven that there is a strong direct correlation between the extent of the neutrophil infiltration in the ischemic tissues and the area of capillaries that fail to be reperfused, which was corroborated by the observation that the no-reflow phenomenon is almost totally abolished by neutrophil depletion in the heart, brain, and skeletal muscle.54

Leukocyte infiltration brings about the capillary no-reflow phenomenon mainly by 3 mechanisms: leukocyte impaction in the capillaries, formation of edema, and the production of oxidant species.

In the first mechanism, the notion that leukocyte impaction contributes to this phenomenon resulted from the observation that these stiff and large cells must undergo significant deformation to enter and travel through the small capillary networks. Given the low pressure that drives blood through the capillaries and the low pH during ischemia (which increases the stiffness of leukocytes), there is a higher probability of leukocyte impaction that blocks reperfusion upon restoration of circulation.54

The second mechanism, formation of edema under ischemic conditions, results from disruption of the neutrophil-dependent microvascular endothelial barrier. As a result, fluid and proteins leave the vessels according to their gradients and accumulate in the tissues, causing edema. This formation of edema secondary to neutrophil-dependent was shown to increase in vascular permeability and contributed to the genesis of no reflow in a skeletal muscle model.55 Formation of edema has been associated with a marked decrease in the number of patent capillaries, and treatment with phalloidin and hyperosmotic saline-dextran solution (which alter the gradient between the blood and the tissues and impede fluid flow to the interstitial space) have been shown to prevent edema formation and to attenuate the reduction in the number of patent capillaries.55

However, changes in external pressure are not the only cause of vessel closure. The third mechanism, active vasomotility, also plays an important role in the development of no reflow through the release of oxidant species by infiltrating leukocytes, which have a powerful vasoconstrictor effect, as discussed previously. In an animal model, treatment with L-arginine alone or in combination with antioxidative vitamins prior and during a limb ischemic episode reduced interstitial edema by 31% and 40%, respectively, prevented microvascular constriction, and preserved blood flow after reperfusion without development of the no-reflow phenomenon.56

Preventive and Therapeutic Approaches to Warm Ischemic Damage
Although the general mechanisms of cell ischemic damage have been extensively studied, donor pretreatment to prevent and mitigate warm ischemic injury is still under investigation. Clinically trialed interventions to achieve this goal are scarce, especially in the context of DCD. Timely identification of potential DCD, accurate assessment of the probability of transplant success for each donor, in situ oxygenated recirculation under normothermic or hypothermic conditions, ex vivo machine perfusion, and cold storage with different solutions are thus far the implemented methods of improving utilization rates.

Identification and assessment of potential donors after circulatory death
As discussed previously, the implementation of DCD programs is the most effective way to increase organ donation and transplants.5 In these programs, and because of the special conditions that involve these types of donors, criteria for the identification and validation of the donors must be accurate and under constant review so as to identify potential pitfalls and improve identification and utilization rates.

In the context of controlled DCD,11 the time between WLST and cardiac arrest is one of the most important parameters to assess the suitability of the donor’s organs for transplant and is related to the degree of hemodynamic and respiratory support and the patient’s respiratory, neurologic, and circulatory condition.57 Several studies have attempted to identify possible variables that predict a rapid death after WLST (maximum 2 h after WLST, depending on the organ). Controlled mechanical ventilation, norepinephrine administration, absence of brain reflexes, neurologic deficit, and absence of cardio­vascular comorbidities have been identified as independent risk factors for cardiac death under 60 minutes after WLST in a prospective study from the Netherlands.13 The United Network for Organ Sharing critical pathway for donation after cardiac death suggests ventilatory support for respiratory insufficiency, mechanical circulatory support, severe disruption in oxygenation, pharmacologic circulatory assist, intra-aortic balloon pump, and inotropic support as indicators of probable death under 60 minutes after WLST.58 All of these criteria can be used to accurately identify and assess the probability of successful organ retrieval and transplant. However, a solid and validated scoring instrument for the objective assessment of potential DCD still does not exist and should be a topic of research in this area.

In situ oxygenated recirculation
In DCD (especially in an uncontrolled setting), warm ischemia times are far higher than in DBD and, as such, there is a much higher probability of ischemia-reperfusion injury to the graft. Therefore, it is important to somehow maintain oxygenation of the organs between patient death (with consequent cessation of circulation) and organ retrieval. With the growing implementation of DCD programs to expand the donor pool, attention has been drawn to the development and study of new organ preservation methods in these settings, namely, hypothermic and normothermic regional perfusion (NRP).

In the context of DCD, there is normally a no-touch period with varying duration between different countries (extending from 5 to 15 min). After this, vessel cannulation of the vessels is performed and extracorporeal circulation is initiated. Again, there is an enormous variations in inclusion criteria and in techniques used in different centers: surgical versus percutaneous cannulation, extra­corporeal membrane oxygenation versus standard bypass, continuous versus pulsatile circulation, occlusion of the aorta versus nonocclusive methods, and so forth. These regional and national differences in protocols, whether because of local preferences in techniques or because of different legal frameworks, prevent a completely objective comparison in terms of outcomes.

Abdominal hypothermic oxygenated recirculation
Abdominal hypothermic regional perfusion (AHOR) was developed to meet the potential benefits of organ maintenance under hypothermic conditions, that is, more efficient cooling, reduced warm ischemia, and continuous gas exchange. The technique involves cooling the perfusate (diluted blood solution) to a temperature ranging from 4 ºC to 20 ºC and maintaining recirculation from the end of the no-touch period to surgical organ retrieval. Despite continuous gas supply to the reperfused organs, after 20 minutes of hypothermic recirculation, oxygen consumption is minimal, owing to the decrease in metabolic processes caused by the sub-normothermic temperatures.59 In comparison to ANOR, this is one of the major potential advantages of AHOR.

The clinical results of this technique vary considerably between different reports: initial graft function ranges from 9% to 35%, DGF from 21% to 85%, and PNF from 4% to 6%.60-63

Abdominal normothermic oxygenated recirculation
Normothermic regional perfusion has the undeniable advantage of maintaining normal cell metabolism without the deleterious effects of ischemia. To the organ itself, it is as if the donor’s heart is still beating and consequently all of the aforementioned mech­anisms of cell injury are stopped at its start. Cell integrity is preserved, and it is expected that overall organ function follows suit.

The efficacy of NRP in comparison with static cold storage (SCS) and in situ perfusion in DCD has been established, both in short-term outcomes such as PNF and DGF and in overall graft survival at 1 year posttransplant,64-66 placing NRP as the undoubtedly preferred method of organ preservation and donor conditioning in DCD. Despite this, high-quality evidence comparing the short-term and long-term efficacy of AHOR and ANOR is still scarce, and further research in this area is warranted.

Ex vivo machine perfusion
Organ preservation after the cessation of circulation and organ retrieval has been intensively studied since the middle 19th century, when the first attempt to perfuse an isolated organ was made.67 The concept of organ perfusion after death was successively redefined and improved with the use of small pumps and whole blood as the perfusate,68,69 until 1967, when a combination of continuous perfusion and hypothermic organ storage was designed, allowing 72-hour preservation of canine kidneys.70 However, because several studies failed to prove any benefit from machine perfusion compared with SCS,71 since the early 1980s, most recovered kidneys have been preserved through SCS alone, with improving success rates owing mostly to enhanced preservation solutions and recipient immunosuppressive therapy.

Nowadays, most transplanted kidneys retrieved from both DCD and DBD are maintained under SCS, mostly due to the much easier handling and preparation of the organs. Despite this, the use of machine perfusion (especially in the context of DCD, where ischemic damage is a far greater concern than in DBD) is increasing, owing both to the solid evidence of the superiority of machine perfusion compared with SCS and to the increasing number of DCD and its importance to the overall transplant paradigm. A recent Cochrane systematic review concluded that, compared with SCS, hypothermic machine perfusion reduces the rate of DGF in kidneys obtained from deceased donors. Moreover, it results in increased survival of the transplanted kidney and overall cost savings.72 However, insufficient data have prevented the study of normothermic machine perfusion and its comparison to hypothermic machine perfusion.

Future Perspectives in Organ Preservation
Organ transplantation is still a developing area of medicine, and research in this field is of crucial importance. Although the mechanisms of ischemia are now understood, little to no direct therapy aimed at these specific mechanisms has been well studied or is being employed at the moment. Tackling these mechanisms and improving donor detection and organ preservation methods are among the most important milestones to be achieved in organ transplantation.

Control of coagulation was one of the first proposed methods to decrease ischemia-reperfusion injury. Theoretically, heparin administration would prevent macrovascular and microvascular thrombosis, which would mitigate the no-reflow phenomenon. However, it has been shown that little to no microvascular thrombosis occurs in this context,54 and the effect of heparin administration on graft function is still under intense discussion in the transplantation community.73 Moreover, the pre-mortem administration of heparin is ethically questionable because it has no benefit and could hasten the death of the patient.74

Ischemic preconditioning, although feasible and effective in living donor transplant and DBD,75 faces the same ethical issues as the administration of heparin, where intervention aimed at improving transplant outcomes in the not-yet-dead donor is troublesome from a moral point of view.

Conclusions

Overall ischemia time is still the major determinant of organ viability in the context of organ donation from deceased donors. Understanding the patho­physiology of warm ischemia and its differences from cold ischemia and finding ways to decrease its time to the least possible value, along with donor conditioning that mitigates warm ischemia mechanisms, will optimize organ viability. This is particularly important in DCD, where ischemia times are unpredictable and may preclude organ transplant.

Coupled with legal and social changes that have allowed all forms of organ donation (DBD and controlled and uncontrolled DCD) and proper donor identification and assessment for organ transplant, this understanding and mitigation of warm ischemia can greatly increase the number and success rates of kidney transplants.

Keeping the status quo on this matter will result in a large proportion of patients on the organ transplant wait list never being transplanted. Efforts must therefore be made, through scientific research, medical training, and policy changes, to maximize the number and the success of kidney transplant surgeries, which is the only hope for a tremendous number of patients worldwide with end-stage kidney disease.


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DOI : 10.6002/ect.2020.0081


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From the 1Faculty of Medicine of the University of Porto, the 2Departament of Surgery and Physiology, Faculty of Medicine of the University of Porto, and the 3University Hospital Center of São João, Porto, Portugal
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no potential declarations of interest.
Corresponding author: Francisco S. Dias, Faculty of Medicine of the University of Porto, Porto, Portugal
Phone: +351 936260342
E-mail: francisco.santos.dias@outlook.com