Effect of Antioxidant in Preservation Solution on Kidneys

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1		Aneta Ostróżka-Cieślik	--	2935	2022-04-29 10:01:09	\|
2	Reference format revised.	Lindsay Dong	Meta information modification	2935	2022-05-05 06:33:24	\|

This entry is adapted from the peer-reviewed paper 10.3390/ijms23063141

Ischemia–reperfusion injury is a key clinical problem of transplantology. Current achievements in optimizing organ rinse solutions and storage techniques have significantly influenced the degree of graft damage and its survival after transplantation.

renal transplantation antioxidants organ preservation solution

1. Ischemia-Induced Organ Damage

Maintaining vital functions of the organ outside the donor’s organism is a complex process. Organ ischemia may induce irreversible changes leading to acute rejection, primary or delayed graft function, or initial poor graft function. Damage can be generated in three stages: during disorders of homeostasis and distribution of blood flow through the organ in the donor’s body, during warm (WIT) and cold (CIT) ischemia time, and during reperfusion. The warm ischemia time is the period between the interruption of the blood supply to the organ and the beginning of cold storage. Current in situ techniques of organ cooling practically enable the elimination of the warm ischemia time. However, warm ischemia may occur after cardiac arrest prior to organ procurement. Cold ischemia, in turn, is associated with the period of organ storage by simple hypothermia or constant perfusion ^[1]. The extent of damage is related to the time that elapses until the organ reperfusion—that is, restoration of circulation.

During ischemia, cells are deprived of oxygen, and anaerobic transitions are activated, which leads to the accumulation of toxic transformation products. Currently, the aim is to quickly cool the organ after procurement, rinse the blood off the vascular system, and fill the vascular bed with an organ preservation solution ^[1]^[2]^[3].

During ischemia, mitochondria are damaged. Their swelling and a change in mitochondrial permeability transition are observed. Stopping aerobic respiration leads to the inhibition of the oxidative phosphorylation process, the exhaustion of high-energy adenosine triphosphate reserves (ATP), and a decrease in the activity of active transport systems and cell membrane potential. The electrolyte composition of the intracellular fluid changes. The sodium–potassium pump becomes inefficient, which means that potassium leaves the cell and sodium enters it ^[4]. Phosphates (HPO₄²⁻) are released into the extracellular fluid. The penetration of sodium and chlorine into the cell increases its osmolarity, and as a consequence, leads to the inflow of water and cell swelling ^[1]^[5]. The concentration of Ca²⁺ ions increases within the cell. Cell-damaging enzymes are induced, i.e., phospholipases, lysosomal hydrolases, endonucleases, proteases, ATPases ^[6]^[7]. Transition to the anaerobic pathway results in the retention of H⁺ ions, lactates, and CO₂ in the cell and causes its acidification. Lowering the pH in cytosol causes instability of lysosomes, blocks the activity of lysosomal hydrolases, and changes mitochondrial properties. Cytochrome c is released into the cytoplasm, which in turn can lead to cell apoptosis or necrosis ^[4]^[8]^[9]. Acidosis may cause dissociation of transition metals (mainly iron) from binding proteins that catalyze free radical formation. Reactive oxygen species (ROS) can be generated during ATP degradation in the initial phase of ischemia in both the intra- and extracellular space. ROS cause lipid peroxidation of cell membranes, damage of lysosomal membranes, and activation of epithelial cells ^[9]^[10].

2. Antioxidants with a Potential Nephroprotective Effect

Currently, two methods are most commonly used to store organs: by simple hypothermia (the so-called simple cold storage—SCS) and continuous perfusion in hypothermia by vessels using a special pump—HMP (hypothermic machine perfusion) ^[11]. The first method consists in rinsing the blood off the veins with a cold preservation solution (temperature of 4 °C), which prevents the blood from clotting in the organ and slows down metabolism within the cell, tissue, and organ. Organ cooling reduces the degradation of tissues, reduces the rate of enzymatic reactions, and slows down the consumption of ATP resources ^[12]. The method of continuous pulse perfusion in hypothermia requires the use of a perfusion device in which the pump pumps the cold preservation solution (4 °C) through the vascular system of the organ in a continuous manner until the time of transplantation. The cooled solution is pumped through the organ’s artery, and after flowing through the organ, it flows out through the vein. This cycle is repeated in the closed pumping system. This method enables regulation of the energy metabolism of the organ and facilitates the elimination of toxins. It also allows for interference in the innate immune response of cells ^[13]. The conducted research confirms that the use of HMP reduces the frequency of delayed graft function (which minimizes the need for dialysis), shortens the patient’s stay in hospital, and improves graft survival ^[14]. Currently, portable systems are available on the market that enable kidney transport under conditions of continuous perfusion in hypothermia (Organ Recovery Systems—LifePort). The device allows for the analysis of hemodynamic (flow, resistance) and biochemical parameters of the organ. The time of storing the kidney in the container is up to 72 h ^[13]^[15]. There is advanced research on the possibility of storing kidneys and liver by HMP and by normothermia at 37 °C (NMP—normothermic machine perfusion). Both HMP and NMP methods have numerous advantages and disadvantages. Organ storage by normothermia would reduce organ damage resulting from ischemia during hypothermia. Maintenance of the organ under physiological conditions would also allow a determination of the vital functions of the graft and extend the time of its safe storage. The disadvantage of this method is the need to continuously supply oxygen/oxygen carriers during organ storage. The time of cold ischemia should be as short as possible, which should limit the deteriorating organ functions.

2.1. Potential Mechanisms of Antioxidant Action

The action of antioxidants during ischemia–reperfusion may proceed in three directions. Antioxidants may inhibit oxidation reactions by scavenging reactive oxygen species and oxygen free radicals. These compounds can inhibit the release/action of transition metals that catalyze the Fenton and Haber–Weiss reactions. Antioxidants can activate protein phosphorylation reactions and activate transcription factors that encode the synthesis of enzymatic and non-enzymatic antioxidants. Determining the mechanisms of antioxidant action faces many difficulties due to the complexity of the multifaceted sources of oxidative stress and their dynamic interrelationships ^[16]. During oxidative stress, ROS are generated in various kidney cells (endothelial, mesangial, and tubular cells) and in the intracellular and extracellular environment, which hinders the therapeutic direction of antioxidants. On the other hand, complete inhibition of ROS signaling could disrupt mechanisms for maintaining cellular homeostasis. For example, complete removal of hydrogen peroxide would impair hemodynamic function ^[16]. Mitochondria have been identified as a key source and target of excessive ROS production. Currently, many studies are being conducted to develop a therapeutic strategy targeting mitochondria (e.g., a derivative of CoQ10, termed MitoQ, and α-tocopherol-conjugated triphenylphosphonium). The ability of the mitochondrion to build H⁺ transmembrane potential for supporting ATP synthesis is used for this purpose. The hydrophobic part of the compound carrying the positive charge, delocalized on conjugated double bonds, enables the introduction of the antioxidant into the mitochondria ^[17]. Polyphenolic compounds (e.g., resveratrol, quercetin) show the ability to scavenge ROS, up-regulate Nrf-2 (nuclear factor erythroid 2-related factor 2) signaling, and prevent the release of pro-inflammatory HMGB1 (high mobility group box protein 1) in the circulation ^[18]^[19]. The antioxidant properties of bioelements are primarily determined by their role as a component of the active center of antioxidant enzymes (e.g., selenium-dependent glutathione peroxidase, and copper and zinc superoxide dismutase).

2.2. Bioelements: Selenium and Zinc

Selenium and zinc influence the maintenance of the correct oxidoreduction balance of the organism. Proper supplementation with these elements significantly influences the correct course of treatment of many chronic metabolic diseases. Selenium is a component of two key amino acids (selenomethionine and selenocysteine) and antioxidant systems with catalase (CAT), superoxide dismutase (SOD), glutathione (GSH), vitamin E, carotenoids, and ascorbic acid. However, the choice of effective selenium supplementation is a complex problem. It results from the narrow therapeutic range of Se (small difference between therapeutic and toxic doses) and the dependence of its action on the chemical form used. A daily selenium intake of 55–70 μg is recommended. This amount is necessary for maintaining optimal glutathione peroxidase (GPX) activity in the body ^[20]. Selenoproteins are involved in oxidative stress reactions in all cell types. This group of proteins includes glutathione peroxidases (catalyze reduction reactions of hydrogen peroxide and organic peroxides), iodothyronine deiodinases (involved in thyroid hormone metabolism), and thioredoxin reductases (protect cells from oxidative stress) ^[21]. Selenium has been suggested to potentially affect ROS-dependent pathways ^[22]. Zinc affects the oxidative-reductive status of cells as a component of superoxide dismutase, which is involved in the neutralization of the superoxide radical. It delays oxidative processes by inducing the expression of metallothioneins acting as free radical scavengers. It shows anti-inflammatory effects and takes part in tissue regeneration ^[23]. The average zinc requirement is 10–15 mg/day.

2.3. Vitamin C

Vitamin C (ascorbic acid) is a hydrophilic compound, located in the cytoplasm. It is a strong extracellular and intracellular antioxidant, participating in a number of metabolic processes. It contributes to maintaining the redox balance of the cell by participating in the reduction in superoxide anion radical and hydroxyl radical production, protects against lipid peroxidation and development of inflammation in organs, and supports the immune system by stimulating the production of T lymphocytes and natural killer cells ^[24]. Together with coenzyme Q and glutathione, it protects mitochondria from oxidative stress. It shows beneficial effects on endothelium (scavenges superoxide anion radical, releases NO from S-nitrosothiols, and stimulates the increased synthesis of citrulline in endothelial cells). It participates in the reconstruction of α-tocopherol and β-carotene from their radical forms ^[25]^[26]. It has been suggested that it affects DNA repair by regulating the activity of repair enzymes ^[27]. In high concentrations, vitamin C can act as a pro-oxidant, promoting oxidation reactions of copper and iron. This can lead to the formation of superoxide and hydroxyl radicals ^[28]. It is an important antioxidant of extracellular fluids and an important intracellular antioxidant ^[29]^[30].

2.4. Vitamin E

Vitamin E is a hydrophobic compound, located in the cell membrane. Its predominant form in tissues is α-tocopherol ^[31]. It shows the ability to inhibit lipid peroxidation, thus protecting mitochondrial membranes from oxidative damage. Its antioxidant capacity is mainly due to its ability to deactivate oxygen singlet by quenching. It is also an inhibitor of the lipid peroxidation chain reaction, leading to the formation of the α-tocopheroxyl radical (α-TO^•) ^[32]. This radical can be reduced back to its active form by ascorbate. It is suggested that the combination of vitamins C and E enhances the antioxidant effect ^[33]. Trolox (6-hydroxy-2,5,7,8-tetra-methylchroman-2-carboxylic acid) is a synthetic, hydrophilic analogue of vitamin E. It exhibits the ability to penetrate biological membranes. It protects cells from oxidative damage ^[34].

2.5. Carnitine

Carnitine is a vitamin-like substance or “quasi-vitamin”. It has the ability to counteract oxidative stress. It plays an important role in energy production. It participates in the transfer of long-chain fatty acids from the cytosol into the mitochondrial matrix, where beta-oxidation takes place ^[35]^[36], regulates nitric oxide levels, increases the activity of enzymes involved in antioxidant defense (glutathione peroxidase, catalase, and superoxide dismutase) ^[37], and reacts with superoxide and hydrogen peroxide. It shows the ability to chelate iron ions. L-carnitine can stabilize membranes. It prevents lipid peroxidation and DNA cleavage ^[38]^[39].

2.6. Flavonoids

Flavonoids are plant-derived compounds composed of two aromatic rings joined by a pyran or pyrone ring ^[40]. The main flavonoid classes include flavones (e.g., luteolin), flavanols, flavonols (e.g., kaempferol, quercetin, fisetin), flavanones, and anthocyanidins. They exhibit antioxidant activity by several mechanisms. They prevent the formation of reactive oxygen species (ROS) by inhibiting the activity of enzymes involved in their production. They act as chelating agents for transition metal ions (mainly iron), reducing the concentration of ROS. They have the ability to capture free oxygen radicals (superoxide anion radical, superoxide radical, hydroxyl radical) and to quench singlet oxygen. They inhibit lipid peroxidation processes by interrupting cascades of free radical reactions ^[41]^[42]^[43]. They have been suggested to be effective in the prevention and therapy of acute kidney injury (AKI) and chronic kidney disease (CKD) ^[44].

2.7. Resveratrol

Resveratrol (3,4′,5-trihydroxy-trans-stilbene, RSV) is a natural polyphenol that belongs to the class of stilbenes ^[45]. Stilbenes are a group of polyphenols composed of two phenolic rings, connected by a two-carbon methylene bridge. RSV exhibits lipophilic characteristics. It is a strong antioxidant that scavenges mitochondrial reactive oxygen species and diminishes quinone-reductase-2 activity. It may increase the activity of superoxide dismutase (SOD) and glutathione peroxidase (GPx), enhance the potential of mitochondrial membrane and ATP levels, and decrease the level of malondialdehyde (MDA) ^[46]^[47]. Its action is related to the modulation of many cellular processes. It increases the activity of the adenosine monophosphate (MP)-activated protein kinase (AMPK). AMPK can phosphorylate and activate PGC1α (peroxisome proliferator-activated receptor-γ coactivator-1α), which promotes mitochondrial biogenesis ^[48]. It is a potential tool for regulating SIRTs (sirtuins), histone deacetylases regulatory enzymes of genetic materials. Resveratrol can reduce inflammation and oxidative stress by activating Nrf2 (nuclear factor (erythroid-derived 2)-like 2) and SIRT1 (silent information regulator T1) signaling. It reduces the stimulation of the NF-κB (nuclear factor κB) and the release of endogenous cytokines ^[49]^[50].

2.8. Tanshinone IIA

Tanshinone IIA (TIIA) is a lipophilic diterpene extracted from the root of Salvia miltiorrhiza. It exhibits anti-inflammatory activity and prevents oxidative stress and apoptosis. It decreases the levels of malondialdehyde (MDA) and oxidized low-density lipoprotein (oxLDL) and increases the activity of glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase ^[51]. It decreases H₂O₂ levels and reduces the accumulation of reactive oxygen species (ROS) ^[52]. It stabilizes vascular endothelial function and inhibits expression of inflammatory cytokines IL-1β and TNF-α ^[53].

2.9. Lecithinized Superoxide Dismutase (Lec-SOD)

Lecithinized superoxide dismutase (lec-SOD; lecithinized human copper/zinc SOD) is a modified form of SOD showing high clinical efficacy. SOD therapy is not very effective due to its short half-life (approximately 6 min), low stability in plasma, and low affinity for the cell membrane. Lec-SOD shows high affinity with cell membranes, high stability in plasma, and higher pharmacological activity ^[54]^[55]^[56]. It exerts antioxidant and anti-apoptotic effects. By scavenging free oxygen radicals, it protects against the toxicity of reactive oxygen species ^[57]. It inhibits the increases in the expression of markers of fibrosis α-smooth muscle actin and collagen ^[58].

2.10. Mitoquinone

Mitoquinone (MitoQ; 10-(4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadien-1-yl)decyl triphenylphosphonium) is a synthetic derivative of coenzyme Q10. It is a potent therapeutic antioxidant with a ubiquinone moiety attached to a lipophilic triphenylphosphonium/TPP+ cation. It belongs to the family of mitochondria-targeted antioxidants (>90% of the compound is bound to the mitochondrial membrane) ^[59]. MitoQ reduces mitochondrial oxidative stress and inhibits lipid peroxidation by blocking hydroxyl radical attack. It is characterized by high bioavailability. Currently, the FDA has not yet approved MitoQ as a drug ^[60]^[61].

2.11. Edaravone

Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one, MCI-186, Radicut^®) is a synthetic, potent free radical scavenger. It was developed in Japan by Mitsubishi Tanabe Pharma Corporation and introduced into therapeutics in 2001. Radicut^® is a drug used in therapy to treat acute ischemic stroke (AIS) patients ^[62]. In 2017, it was approved by the U.S. Food and Drug Administration (FDA) for the treatment of ALS (amyotrophic lateral sclerosis) ^[63]. Edaravone shows the ability to quench hydroxyl radical and inhibit hydroxyl radical-dependent and hydroxyl radical-independent lipid peroxidation. It inhibits peroxyl radical-induced peroxidation systems. It is suggested that its effectiveness corresponds to the action of the system: vitamin C with vitamin E ^[64]. Edaravone prevents mitochondrial oxidative stress ^[65] and protects endothelial cells against damage by reactive oxygen species ^[66]. Edaravone reduced cold I/R injury in a canine kidney autotransplantation model ^[67]. Kidneys were stored 72 h in cold HTK fluid modified with edaravone at a dose of 50 μM. It was additionally applied at harvest and at reperfusion (3 mg/kg). Edaravone suppressed lipid peroxidation in renal tubular cells and ameliorated kidney dysfunction. The agent inhibited P-selectin expression in renal endothelial cells, improved renal vascular resistance, and maintained renal tissue blood flow. Edaravone increased urine production and Cr clearance. The agent lowered the mean serum creatinine.

2.12. Nicaraven

Nicaraven (N,N′-propylenebisnicotinamide; AVS) is an antioxidant that exhibits hydroxyl radical scavenging activity in vitro. The agent has hydrophilic and lipophilic chemical properties. One molecule of nicaraven directly neutralizes two hydroxyl radicals by intramolecular π-dimerization. Nicaraven has the ability to suppress lipid peroxidation ^[68]. The drug prevents vascular constriction ^[69].

2.13. Propofol

Propofol is a lipophilic antioxidant and a widely used anesthetic. The agent has a chemical structure that is similar to alpha-tocopherol (which also contains a phenolic OH-group). It has been suggested that it may prevent lipid peroxidation in cell membranes and that it can be a potent modifier of biomembranes ^[70]^[71]. The drug scavenges reactive oxygen species (ROS) to generate less reactive phenoxyl radicals ^[2].

2.14. Deferoxamine

Deferoxamine (Desferrioxamine, DFO) is a bacterial siderophore produced by Streptomyces pilosus. The drug chelates free iron ions in a 1:1 ratio (forming a ferixamine complex), making it a potential modulator of the oxidative stress involved. Iron catalyzes reactive oxygen species (ROS) directly via the Fenton and Haber–Weiss reaction. The Fenton reaction is between ferrous ion (Fe²⁺) and hydrogen peroxide (H₂O₂), which is mainly produced by superoxide dismutase (SOD) ^[72]^[73]^[74]. DFO stabilizes HIF-1α (hypoxia-inducible factor-1α) under normoxic conditions ^[75].

2.15. PrC-210

PrC-210 aminothiol (3-(methyl-amino)-2-((methylamino)methyl)propane-1-thiol) is a potent antioxidant that can be used intravenously, orally, and topically, showing few side effects ^[76]. Aminothiol has a small molecular size, which allows for efficient transmembrane diffusion. Amines on an alkyl backbone enable strong ionic interaction with DNA and scavenging of ROS around DNA. PrC-210 scavenges recurrent oxygen species and protects plasmid DNA from ROS-induced damage ^[77]. It has been observed that the PrC-210 minimizes the risk of cell death in myocardial infarctions in a mouse model after I/R ^[78]. The antioxidant effect of PrC-210 is dose-dependent. Its ROS scavenging capacity was found to be optimal in the dose range of 0.5 mmol/L–2.3 mmol/L. PRC-210 has the advantage of rapid (within seconds) and long-term antioxidant activity (up to several hours). Its disadvantage is its limited applicability after the damage has occurred. PRC-210 has shown high efficacy in damage prevention ^[76]. In humans, it has a radioprotective effect against lethal radiation dose ^[79].

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