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Volume: 19 Issue: 6 June 2021

FULL TEXT

REVIEW
Organ Preservation Solutions in Transplantation: A Literature Review

Abstract

In this review, our objective was to identify and compare the most commonly used organ preservation solutions and discuss results of studies with additives to these solutions and with experimental solutions. An integrative literature review was carried out by selecting relevant publications on preservation solutions used in organ transplant via electronic searches in PubMed, the Scientific Electronic Library, the Latin American and Caribbean Literature in Health Sciences, and MEDLINE databases. In total, 275 articles were collected, of which 52 papers were considered based on the inclusion criteria. Although there are established preservation solutions among medical transplant teams, such as Collins, University of Wisconsin, IGL-1, histidine tryptophan-ketoglutarate, and Celsior, these solutions still have functional limitations on protection against ischemia-reperfusion injury. Therefore, new substances and alternative methods of conservation have been researched.
The present paper found several experimental solutions, additives, and micronutrients with great potential for preserving grafts and minimizing ischemia-reperfusion injury, emphasizing the importance of continued research into alternatives to standard solutions.


Key words : Conservation solutions, Graft survival, Graft rejection, Ischemia, Primary graft dysfunction, Transplantation tolerance

Introduction

In 2017, 139?024 organ transplants were performed worldwide according to the Global Observatory on Donation and Transplantation of the World Health Organization. However, the number of organs is insufficient to meet the demand, leaving thousands of people on wait lists and barely covering 10% of local needs. Organ transplantation is frequently associated with ischemia-reperfusion injury (IRI); thus, many methods (such as static cold storage, perfusion machines, and pharmacological conditioning) have been formulated to reduce the morbidity related to IRI and to improve the maintenance of tissue viability.1,2 Hence, preservation techniques and perfusion solutions are the main targets of current research on organ conservation. Since the 1960s, static cold storage has been considered the gold standard for organ preservation, given that a hypothermic environment is considered to reduce cellular metabolism; along with static cold storage, preser­vation solutions can also promote cytoprotection.3

Reevaluation of advantages and limitations of each preservation method can aid in the development of new solutions, which could allow safer and longer conservation, thus having the potential to increase the number of available organs.3 Our present review aimed to identify and compare the preservation solutions most commonly used and to discuss the result of studies in which additives were used along with those solutions, as well as the applicability of experimental solutions.

Method for Literature Review

The literature review was conducted according to the Preferred Reporting Items in Systematic Reviews and Meta-Analysis.4

The online research was conducted using PubMed, Scientific Electronic Library, Latin-American and Caribbean Health Science Literature, and MEDLINE databases. Medical subject heading (“MeSH”) descrip­tors were used in the strategy, combined with Boolean operators, to create the following searches: “organ pre­ser­vation” AND “organ preservation solution” AND “transplantation”. No language filter was applied.

As inclusion criteria, only fully published online original papers and reviews published between January 1, 2017 and December 31, 2019, in which the object of study was conservation solutions for organ transplant, were considered. Exclusion criteria included research published outside of the selected time period, studies outside of the proper approach to the central subject, and studies with little to no information on the proposed theme. The process of identification, eligibility, and inclusion of articles is shown in Figure 1.

Results and Discussion

Table 1 summarizes the identified advantages and shortcomings of the 13 conservation solutions (the 7 mostly used solutions in clinical practice and 6 alternative fluids) included in this review.

Most Commonly Used Solutions in Clinical Practice

Collins solution and Euro-Collins solution

Collins solution was the first preservation solution to be commercialized (in 1969) and has been used for preservation of organs such as kidneys, heart, liver, and pulmonary patches. In 1980, its composition was improved, adding impermeability; the new solution was named Euro-Collins. Euro-Collins has the advantage of offering better protection during prolonged cold ischemia, thus allowing broader use in current surgical practice.3

University of Wisconsin solution

University of Wisconsin (UW) solution, considered a gold standard solution, is widely applied in the conservation of abdominal organs.5 Raffinose, a hydroxyethyl starch, used to prevent edema, and lactobionate, a gluconate with antioxidant components, are the 2 main ingredients of UW solution.3,6 This solution is also characterized as an intracellular fluid solution, given the low sodium and high potassium concentrations.7,8 University of Wisconsin solution has been mostly used to preserve abdominal patches, such as the pancreas, in which UW solution has been shown to have better results after cold storage.7 A modified UW solution (UW-gluconate) has been mostly used in experimental perfusion machines, given that the necessary substrates for hepatic metabolism are not present in its composition.9 In addition, the standard UW solution provides better conservation of patches through prolonged cold ischemia, despite higher levels of biliary stenosis compared with IGL-1 solution (George Lopez Institute solution) and histidine tryptophan-ketoglutarate (HTK).10,11

IGL-1 solution

The IGL-1 solution is a polyethylene glycol (PEG) with low weight of 35 kDa; it has an inverted sodium/potassium concentration and low viscosity compared with the gold standard UW solution.12 When both preservation solutions were compared in a fatty liver patch, the IGL-1 solution helped to prevent a decrease of ATP more effectively than UW solution, ensuing greater inhibition of the ubiquitin-proteasome system and reduction of proteolysis in hepatic tissue.13 Moreover, the low-weight PEG solution offered a result similar to UW solution with regard to kidney preservation,14 delayed graft function, rejection rate, and survival rate for both kidney patches and transplant patients.12

With regard to other frequently applied solutions, a cold storage preservation study of mouse hepatic grafts after 24 hours in IGL-1 showed a larger reduction of apoptosis and expression of the high-mobility protein HMGB1 when compared with grafts conserved in HTK solution.15

The IGL-1 compound, whose benefits include decreased liver damage, oxidative stress, and mitochondrial lesions, mediated by nitric oxide, has been shown to be efficient and safe in liver transplant, along with having advantages in pancreas transplant. With IGL-1, 1 month after pancreas transplant, patient survival rate was shown to be about 95.7% and graft survival rate was about 93.6%.16

Histidine tryptophan-ketoglutarate solution

The HTK solution is composed of low potassium and reduced viscosity and was formulated according to the principle of functional inactivation of organ via removal of extracellular sodium and calcium. This formulation is associated with intense buffering of the extracellular space by histidine hydrochloride, allowing similar electrolytic contents of the extracellular fluid and plasma osmolarity. Despite the potential advantages related to the components, evidence has suggested that HTK solution is strongly linked to premature patch rejection, graft pancreatitis, and loss of the donated organ, ultimately making UW solution the most commonly preferred solution.5

However, HTK solution has been shown to be more efficient with regard to decreases in primary dysfunction rate after liver transplant, thus allowing it to be more prevalent versus the standard UW solution, as it provides a shorter postoperative rest and bigger reduction of biliary complications.17 Combined HTK and UW perfusion seems to facilitate wash-out and rapid cooling of the liver graft, allowing long-term preservation in a UW solution and lower rates of early allograft dysfunction.18 Nonetheless, varied results of preservation solutions have been shown to be caused by donor differences and storage and technical aspects of the transplant; therefore, if these factors were properly controlled, such differences in graft survival would not be as apparent.19

HTK-N: new version of the HTK solution

The new HTK-N solution was first introduced to reduce the limitations present with UW and the original HTK solution; this new solution differs from the conventional because of enhanced antioxidant capacity and cold tolerance via the addition of deferoxamine, which acts intracellularly as an iron chelator, and LK614, an imitator of catalase that catalyzes the reduction of H2O2 into H2O in the cells.20
Histopathological results showed that HTK-N was compatible with previously mentioned standard solutions, without any significant difference. However, the most recent solution has superior preservation efficiency, reduced risks of uncontrolled free radicals and possible toxicity of histidine degradation products, and should prevent energy shortfall and cellular edema.20

Custodiol-N solution

The Custodiol-N fluid is an HTK solution modified by the addition of amino acids and other chemical components; this solution is being investigated in clinical and experimental trials.3 Custodiol-N is composed of tryptophan and mannitol and has a high capacity to remove free radicals with antioxidant properties via positive catalase regulation; thus, in addition to its osmotic effect, it has the potential to reduce hypoxia, oxidative stress, and cellular lesions induced by cold storage.3,8

When the Belzer-UW and Custodiol-N solutions were compared with regard to reduction in the number of apoptotic cells during the conservation of pancreatic tissue, immunohistochemical analysis displayed a significant reduction in the endocrine compartment with Belzer-UW solution. Nevertheless, with regard to the exocrine compartment, there were similar decreases in apoptosis between both solutions during the first 3 hours of storage. With regard to prolonged conservation, Custodiol-HTK solution resulted in delayed alterations in parallel with Belzer-UW solution.21

Celsior solution

Celsior is a type of extracellular solution that has been successfully applied in conservation of heart, lung, liver, pancreas, kidney, and intestinal organs. Celsior solution is mainly composed of lactobionate and mannitol and reduced glutathione, with high buffering capacity against acidosis and presenting less viscosity compared with UW solution, given the lack of colloids, facilitating contact with the microvasculature of patches.12 Similar to HTK solution, Celsior also uses histidine due to its buffering aspect and low potassium concentration, whereas sodium remains significantly higher.3

From an analysis of 187 kidney transplants, the Celsior solution showed results equal to traditional UW solution with regard to delayed graft function and survival 2 years after transplant. In Celsior-preserved patches, the incidence of acute tubular necrosis was relatively lower posttransplant. In addition, reperfu­sion with UW solution can result in a quick injection of a high amount of potassium in the bloodstream, which could result in hypotension and bradycardia; these effects do not occur with Celsior solution.11,22

Furthermore, when UW, IGL-1, HTK, and UW-Belzer were compared with Celsior solution, Celsior solution showed less association with graft rejection, was shown to be the best option for lower rates of early retransplant, and showed higher rates of patient and graft survival.12,18

Alternative Solutions

Conservation of organ and tissue 15 solution (20-kDa polyethylene glycol)

The conservation of organ and tissue 15 (SCOT-15) solution is composed of high amounts of sodium, low amounts of potassium, and contains 20-kDa PEG in 15g/L, as a substitute for hydroxyethyl starch. The SCOT-15 solution was first proposed as an alternative to use of UW solution, due to the lower potassium levels, an element that stimulates vasoconstriction. Compared with UW solution, SCOT-15 solution reduces systemic levels of immune response in 30 minutes after hepatic reperfusion and the incidence of postreperfusion syndrome. In addition, it has resulted in better kidney function during the first 10 days posttransplant, with recovery of liver function not influenced by the type of solution in the same period.2

Carbon monoxide-releasing molecule 401

Carbon monoxide-releasing molecule 401 (CORM-401) is a molecule that releases carbon monoxide (CO) and is sensible to oxidant agents. Under cold and normothermic temperatures in UW solution and with the cardiac perfusion compound PlasmaLyte (Baxter, Canada), the amount of CO released by CORM-401 was similar at both 37 ºC and 4 ºC. However, kidney function was significantly improved with CORM-41 treatment, with higher urine and higher creatinine clearance levels compared with inactivated CORM-401.23

The general protector aspects of CO is possibly explained by 2 different routes: mainly through the reduction of damage-associated molecular patterns, with reduced HMGB1 protein (which starts response of Toll-like receptors), and, because of the reduced expression of these receptors, a better inflammatory response, resulting in less IRI. Therefore, there is reduced renal apoptosis, acute tubular necrosis, and renal hemorrhage, as well as diminished expression of caspase 3 (an apoptotic marker), in kidney tissues treated with CORM-401.23

Amniotic liquid

Amniotic liquid contains 98% water and electrolytes; the remaining part includes proteins, peptides, carbohydrates, lipids, amino acids, hormones, antimicrobe molecules, lactate, pyruvate, and growth factors. Similar to that shown with Ringer lactate, HTK, and UW solution for storage of rat livers at 4 ºC for 12 hours, amniotic liquid demonstrated hepatic protection comparable to other gold standard solutions for organ conservation. There was no evidence of sinusoid dilation, hydrotropic degeneration, or focal necrosis; in addition, its immunohistochemical aspects resembled those found in the other solutions tested. Hence, amniotic liquid was shown to be effective in protecting and preventing cell damage during the process of static cold storage.24

Hypertonic citrate adenine solution

The most used solution to preserve kidney grafts in China, hypertonic citrate adenine (HC-A) solution, is hyperosmolar and based on citrate, with adenine additive to enhance kidney function after circulation and high concentration of mannitol to act as a waterproof protection against cellular edema and oxidative stress. Twenty years after the first application of this substance, the solution was enhanced by the Hospital Shanghai Changzheng, resulting in a new compound, termed HC-A II solution.12

The new compound has a double system, consisting of citrate and phosphate, in order to activate buffering that was improved by reduced magnesium and higher levels of adenosine compared with HC-A. New ingredients were also added, including arginine, tryptophan, and ligustrazine, to stabilize the cellular membrane and protect mitochondrial function. HC-A II solution displayed similar effectiveness and was shown to be safe for kidney conservation compared with HTK solution, therefore suggesting that HC-A II solution is a prominent option for clinical use.12

Ringer solution

Ringer lactate solution is a low-priced physiological fluid available in most health care centers. This solution has demonstrated to sufficiently preserve the vitality of splenic tissue in low temperatures. However, there is still doubt concerning the best temperature to preserve the tissues, despite the common 4 ºC in general refrigerators being apparently adequate to maintain vitality. In animals with good graft function after 4 ºC Ringer lactate preservation, the scintigraphy results were not different from results obtained immediately after splenectomy, confirming the good depuration function the following day after organ extraction.25

Baskent University preservation solution

The new Baskent University preservation solution (BUPS) is composed of electrolytes, raffinose, mannitol, N-acetylcysteine, taurine, adenosine, and ascorbic acid. This solution was designed to mimic extracellular fluid enriched with supplements, and, except for calcium salts, its electrolyte content was inspired by the physiological Krebs-Henseleit solution. Compared with established preservation solutions (UW and HTK in rat and pig models), pathologic evaluation showed that BUPS seemed to be as protective as the standard HTK and UW solutions. Evidence showed that BUPS had cytoprotective effects with lower degree of tubular damage, tubular apoptosis, and tubular epithelial cytoskeletal rearrangement (CSKR). Histopathologic findings showed that both BUPS and HTK were better than UW solution. Rates of tubular damage, tubular apoptosis, and development of CSKR were found to be lower in the BUPS group than the HTK group. Use of BUPS improved preservation efficiency by reducing the risk of uncontrolled free radicals, the possible toxicity of degradation products with taurine, the fast energy deficit, cell edema, and therefore risk of development of tubular CSKR, apoptosis, and tubular necrosis. In addition, both functional and pathologic advantages in rat organ preservation were shown with BUPS.26

Solution Additives

HEMO2life (extracellular hemoglobin M101)

M101 is the active principle of HEMO2life® (HEMARINA), an extracellular hemoglobin obtained from a marine invertebrate, Arenicola marina, an annelid that lives in the sand of beaches and is constantly subject to environmental changes from normoxia to hypoxia in different temperatures. The compound HEMO2life was previously tested in preclinical solid-organ transplant models and has been frequently tested in clinical studies of other organs before being tested on kidney transplantation.27 As an additive during the hypothermic storage of pancreatic grafts in rats, the compound showed high affinity for oxygen and could carry more than 156 O2 molecules, in contrast with the 4-molecule potential of human hemoglobin. This resulted in lower impact of ischemia in pancreatic tissues of rats, in the maintenance of oxidative phosphorylation, in the reduction of oxidative stress, and in necrosis during cold ischemia, along with higher rates of insulin secretion, stimulated by glucose, thus having considerable advantages for human pancreatic tissue and islets.28

Berberine

Berberine is a bioactive alkaloid found in several plants and is broadly used in traditional Chinese medicine. Berberine protects against alterations caused by IRI in all mitochondrial parameters considered, with sustained electrochemical potential and oxygen consumption in many situations. Furthermore, the calcium capacity in the mitochondria, reduced considerably due to IRI, resulted in IRI effects partially recovered via Berberine addition. This substance can also be applied as a viable strategy to restore mitochondrial function and prevent complications related to IRI.29

Bone morphogenetic protein 7

Investigations have shown that activation of proteins involved in neurogenesis and epithelial tubular cells proliferation has an important function in the regeneration of renal tissue after ischemic lesions; bone morphogenetic protein 7 (BMP-7) is the most prominent of these proteins and is commonly produced and released by kidneys. One comparative study concluded that BMP-7, with isolated application or combined with UW solution, showed good kidney conservation due to the greater expression of renoprotection factors and the reduction of epithelial phenotype loss in every stage of cold ischemia. Furthermore, BMP-7, when used exogenously, activated the transcription of mRNA and blocked transcription of mRNA from tumor growth factor beta.30

Perfluorocarbon

These nonpolar fluorine-saturated polycarbonic polymers are capable of dissolving and carrying significantly higher amounts of oxygen compared with human blood because of the 0.15- to 0.2-?m sized micellar structure, which allows microvascular penetration where oxygen via red blood cells is compromised, regardless of temperature adjustments. The compound has been shown to lessen reperfusion damage.31

In a donation after circulatory death liver transplant model of rats with Lewis lineage, higher oxygen levels in hepatic grafts were shown with liquid perfluorocarbon addition to the preservation solution, reducing IRI in the liver and enhancing posttransplant survival rate.32 Nevertheless, because oxygen is reached via passive diffusion, an inequal gradient of oxygen distribution was established when perfluorocarbons were added to the solution. Hence, there is a clear limit to the use of this polymer, considering the greater risk of developing ischemic cholangiopathy.33

The benefits of a vaporized version of the substance in pulmonary grafts along with mechanical ventilation were also studied in animal models. The vaporized version had less obstacles during ventilation compared with animal lungs that were treated with the liquid form; also, oxidative stress was reduced during the early period of cold ischemia, conserving the patch for about 6 hours, along with observed protection to alveolar structures displayed in historical analysis.34

Hydrogen sulfide

Also known as sour gas, hydrogen sulfide is part of the small-molecule endogen gas group. It has shown cytoprotective evidence, including reduced oxidative stress, inflammation, apoptosis, and mitochondrial disfunction caused by IRI.35

In vitro models of kidney IRI showed that, during hypoxic storage, the addition of AP39-donator sour gas to UW solution increased the viability of renal epithelial tubular cells and lowered the rate of apoptosis during IRI, with cytoprotective results at a cold temperature (10 °C) compared with sub-normothermic (21 °C) and hot (27 °C) temperatures. There was also better viability of the preservation solution and probably attenuation of negative side effects of the greater metabolic demand, especially at sub-normothermic IRI.35

Supplementation of AP39 to UW solution also significantly protected the function of cardiac grafts in experiments, measured by quantitative scans, against prolonged cold ischemia reperfusion (24 hours at 4 ºC). AP39 also diminished expression of interleukin 6 (IL-6), IL-1?, and tumor necrosis factor ?, which limited the fibrotic area of the cardiac patch and suggested that addition of small AP39 doses can expand storage time without reducing viability of donated heart tissue.36

With regard to cardioprotective effects, a hydrogen sulfide system with slow liberation and long run effects, named DATS-MSN, was studied in heart transplant models using Sprague-Dawley rats. The anti-inflammatory and protective effects of hydrogen sulfide were mainly shown through the signaling pathway TLR4/NLRP3, with potential to improve survival of cardiac allografts.37

Cardiotrophin 1

Cardiotrophin 1, a member of the IL-6 cytokine group, exerts potent apoptotic effects in hepatocytes, cardiomyocytes, and neural cells, due to signaling pathway activation through signal transductors, which ultimately activate transcription and kinases. Hence, this compound has been used in experiments on graft protection against IRI. In kidney transplant models of Fischer rats that included UW solution for patches preserved at 4 ºC, addition of 0.2 ?g/mL of cardiotrophin 1, when added for preservation at low temperatures, resulted in satisfactory survival rates of animals and preserved renal function, along with diminished presence of posttransplant kidney damage markers.38

Cardiotrophin 1 has also been given orphan drug status by the US Food and Drug Administration for the hepatic protection of IRI lesions inherent to transplant procedures. The European Medicines Agency has also given approval for this cytokine for prevention of IRIs associated with solid-organ transplant.38

Hydrogen

Isogenic and orthotopic liver transplant models in Lewis rats demonstrated that UW solution sup­plemented with hydrogen reduced hepatic lesions, inflammation, hepatocyte apoptosis, mRNA-related lesions, and protein expression, as well as suppressed oxidative stress. Serum and historical analyses also showed that inflammatory alterations were not common at 6 hours after reperfusion, and, even after 12 hours of preservation, hydrogen was still capable of effectively diminishing hepatic lesions.39

Similar effects were shown in a lung transplant model. During cold storage, the addition of hydrogen lessened the inflammatory response, reduced IL-10 concentration, and inhibited intercellular adhesion molecule 1 expression, results that were shown to be reached through blockage of p38 MPAK and nuclear factor ?B.40

In a minipig kidney transplant model for inves­tigation of ischemic lesions, when the procedure took place after renal preservation in HTK solution without hydrogen, the result was always primary organ dysfunction. However, when the same procedure followed conservation in hydrogen-supplemented HTK solution for at least 4 hours, blood circulation was detected in transplanted kidneys and urine production was shown.41

A recent study also concluded that, with addition of hydrogen to Dulbecco’s modi?ed Eagle’s medium solution during tissue culture of osteochondral allografts, there was continued activity of cartilaginous cells and extracellular compounds. Despite the limitation concerning the dependency between the protective effects and the amount of hydrogen, this element indicated a new alternative for preservation of cartilage in vitro.42

Metformin

Metformin, an AMP-activated protein kinase activator, has been added to UW solution (in a study that evaluated the preservation of standard and marginal hepatic grafts of young and old Sprague-Dawley rats), through hypothermic machine perfusion. In grafts that included metformin, long-term, less severe lesions were identified in the liver’s microstructure compared with grafts treated without metformin; in addition, metformin, through hypothermic machine perfusion, significantly reduced inevitable lesions on donated livers, therefore reducing differences between young and old organs.43

Mesenchymal stem cells

Because of their immunomodulatory and anti-inflammatory properties, the benefits of local injection of umbilical cord perivascular cells during pulmonary ablation of patch donors were investigated. With their use, there was a certain reduction of oxidative damage and neutrophil overflow in pulmonary tissues; their addition also avoided thickening of the alveolar walls and conserved pulmonary function. Therefore, mesenchymal stem cells were shown to be capable of preventing damage to lungs and could inhibit inflammatory responses mediated by reactive oxygen species.44

Growth factors

In studies of canine kidney transplant models, a number of effects were shown with addition of growth factors (insulin-like growth factors, epidermal and nerve growth factor, bactenectin-derived peptides, and substance P) to UW solution. These effects included considerable enhancement of graft viability and reduced hydrogen peroxide by tubular cells after 3 days of cold storage, as well as protection of mitochondrial function, prevention of apoptosis, improvement of posttransplant functionality, and prolonged storage period of up to 6 days.8

Signaling pathway inhibitors

The use of small interfering RNAs, oligonucleotides, and specific inhibitors or antagonists represent effective approaches to reach the mechanisms involved in ischemia syndrome and hypoxia. These proteosome inhibitors are a potential strategy to reduce ischemia and hypoxia in liver and heart transplants, as well as to upregulate AMP-activated protein kinase activity, downregulate mammalian target of rapamycin signaling, and influence autophagy.12 Treatment of pulmonary patches with A1AT, a serine-protease inhibitor presently used in emphysema treatment, during ex vivo perfusion improved organ function and promoted lesion repair in injured lungs according to studied markers.45 In addition, a recently developed solution containing a c-Jun N-terminal kinase inhibitor peptide positively affected pancreatic islets after experimental transplant isolation, when compared with standard UW solution.46

Hemoglobin-based oxygen carriers

Hemoglobin-based oxygen carrier (HBOC) methods, which allow excellent oxygen carrying capacity, has been used to overcome the use of red blood cells for oxygen supply in metabolic active kidney tissues during storage. Normothermic perfusion lasting up to 6 hours with HBOC addition has been performed in discarded human kidneys and showed that HBOC did not result in inferior outcomes compared with use of packed red blood cells, with only a small deterioration of functional and histological traits in kidney patches during perfusion. Therefore, evidence favors the use of acellular synthetic oxygen carriers during normothermic perfusion ex vivo.47

Shown to be even more efficient than HBOC, HBOC-201 (HemopureTM), a reticulated bovine hemog­lobin polymer, has been used in transfusions when blood was not immediately available, allowing crossed correspondence, ABO compatibility issues, and infection processes to be avoided. Notwithstanding, there are clear limitations, as blood can provide better protection to grafts in normothermic preservation ex vivo; in addition, HBOC-201 may have a negative proinflammatory effect in cardiac patches, which could ultimately result in severe edema.48

Steroids

The addition of methylprednisolone to perfusion solutions can limit growth of the amount of proinf­lammatory cytokines and can reduce myocardiac edema. Moreover, electronic microscopy analysis has suggested a tendency of enhanced endothelial conser­vation during normothermic ex vivo perfusion in hearts treated with methylprednisolone. Nevertheless, the current results have not shown statistical relevance.49

Micronutrient supplementation and antioxidants

The addition of micronutrients to preservation solutions is innovative, including the introduction of selenium to HTK solutions, which considerably reduces the amount of malondialdehyde in the fluid (which is naturally expanded as a consequence of the growth of free radicals). Another benefit is lung protection during IRI lesions and the longer durability of selenium versus zinc as an additive, indicating better synergism of the antioxidant effects of selenium in solutions.50

In grafts, polyunsaturated fatty acids, including phospholipids, undergo peroxidation during storage; supplementation with a preservation fluid added to an exogen antioxidant such as ascorbic acid can strengthen the antioxidant system in the grafts.51

A study of a uterus transplant model showed fewer ischemic lesions, less free radical growth, and patch protection promotion when the modified HTK solution combined with acetyl L-carnitine was applied for 4 hours at 4 ºC.52

Glycerol

Glycerol, commonly named glycerin and a dehydrant agent, has antimicrobial and antiprotease properties, among other characteristics, making it suitable for long-term storage of corneal tissues and usable in clinical indications when a viable cellular layer is not necessary. Furthermore, glycerol can be safely used in infectious keratitis to preserve the visual acuity and proper integrity of the ocular globe, with acceptable rates of complications, as well as positive visual results, especially when fresh corneal tissue is not available. This additive is promptly available in emergency conditions and has lower cost, making it financially doable for current usage.53

Alteplase

In a clinical donation after circulatory death model, the addition of alteplase in a perfusion solution at the moment of pulmonary graft extraction resulted in excellent gas exchange after pulmonary perfusion ex vivo and less vascular resistance compared with the group treated without alteplase; in addition, all grafts reached the proper criteria for clinical lung transplant. However, differences between groups were not statistically significant, thus concluding that further studies are necessary.54

Conclusions

Since the release of Collins solution, about 50 years ago, significant progress toward ideal graft storage solutions has been made. Four current solutions stand out: the UW solution is the most prominent to date, due to the greater use of intra-abdominal organs as grafts and its efficiency with regard to pancreatic grafts. The other solutions include the extracellular solutions IGL-1 and HTK, with high potential to protect hepatic and renal tissues, and Celsior solution, with results comparable to UW solution in kidney transplant procedures. Moreover, compounds such as SCOT-15, which reduces inflammatory response, CORM-401 and HCA II, especially in kidney preservation, amniotic liquid, via liver protection in cold ischemia comparable to standard solutions, and Ringer lactate, effective in splenic tissue conservation under low temperatures, have all been shown to be promising alternatives. Finally, solution additives, mainly HEMO2life, perfluorocarbons, and hydrogen, as well as the supplementation with micronutrients, in particular selenium, ascorbic acid, and acetyl L-carnitine, have shown beneficial results. However, many studies are still pilot investigations, thus suggesting the necessity for improved research on this topic, especially for compounds in which the active principle has antioxidant and cytoprotective effects, with repair or regeneration capacities during and after ischemic lesion formation.


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Volume : 19
Issue : 6
Pages : 511 - 521
DOI : 10.6002/ect.2020.0506


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From the Universidade do Estado do Pará, Faculty of Medicine, Belém, Brazil
Acknowledgements: The authors have not received any funding or grants in support
of the presented review or for the preparation of this work and have no potential declarations of interest.
Corresponding author: Giulia Silva, Centro de Ciências Biológicas e da Saúde, Universidade do Estado do Pará, Travessa Perebebuí, 2623, Belém, Brazil
Phone: +55 91 999417815        
E-mail: giulia.silva@aluno.uepa.br