Maastricht categories of donation after cardiac death donors.
Kidney transplantation is considered the best treatment for end stage renal failure (ESRF) with longer life expectancy and superior quality of life compared to dialysis therapy [1-3]. However, a major constraint to transplantation is the lack of suitable organ donors. To increase the number of available organs there has been an incentive to use ‘marginal’ donors such as donation after cardiac death (DCD) and expanded criteria donors (ECD), in addition to kidneys from the traditional living and deceased donors [4,5]. Although an important source of organs for transplantation, once transplanted a significant proportion of these kidneys have early graft dysfunction.
There are many attributing factors that influence the outcome of the transplanted graft. Donor and recipient age, creatinine clearance, history of hypertension, poor human leukocyte antigen (HLA) matching, cause of death, ethnicity, the cold ischaemic (CI) time and in the case of DCD donors the warm ischaemic insult have all been described as major determinants of graft function and graft survival . The CI time is perhaps the only modifiable factor that significantly affects graft outcome.
Since the 1970s organ preservation has relied on hypothermic conditions to allow an organ to be preserved outside the body from the time of retrieval until transplantation. This allows the organ to be allocated nationally, to the most suitable and immunologically matched recipient. Nonetheless, hypothermic preservation has its limitations and viability cannot be sustained for an indefinite period of time. Hypothermic preservation has been described as ‘a compromise between the benefits and detriments of cooling’ .
2. Standard criteria donor (SCD)
Deceased organ donors fall into three categories. A standard criteria donor is a deceased donor who is declared brain dead after a stroke or other brain injury. Brain death means that there is the irreversible loss of function of the brain.
3. Donation after cardiac death (DCD) donor
Donation after cardiac death donors (DCD) are donors from which the organs are retrieved after the cessation of circulation due to a cardiac arrest. These organs are regarded as marginal organs due to the warm ischaemic (WI) insult that they receive before the onset of preservation. This WI interval causes a degree of injury that can lead to irreversible damage, resulting in an unfavourable outcome after transplantation. Four classifications of DCD donors have been categorised depending on the circumstances of death and when the organs are retrieved [8,9] (Table 1).
|1||Dead on arrival||Uncontrolled|
|3||Awaiting cardiac arrest||Controlled|
|4||Cardiac arrest while brain death||Controlled/uncontrolled|
Maastricht type 1 and 2 donors are patients who have died suddenly from a cardiac event or trauma and therefore are usually based in the Accident & Emergency department. After a failed resuscitation, the patient is pronounced dead and a 5 minute ‘hands off’ period allowed to lapse. The organs are perfused
Maastricht type 3 and 4 are patients who are based on an intensive care unit after a severe brain injury. The patient does not meet the criteria for brain stem death and will maintain spontaneous ventilation. Under controlled conditions with no possibility of recovery withdrawal of treatment is planned. After the cessation of the heartbeat the patient is transferred to the operating theatre and the kidneys retrieved after
4. Expanded criteria donors (ECD)
Expanded criteria donors (ECD) are defined as any brain dead donor aged ≥ 60 years or over 50 years with ≥ 2 of the following conditions; Hypertension, terminal serum creatinine equal or greater than 132µmol/L or death resulting from an intracranial haemorrhage.
5. Cold ischaemic injury
Hypothermic preservation is based on the principle that cooling an organ inhibits the enzymatic processes. There is a 2-3 fold decrease in metabolism for every 10°C reduction in temperature [11,12]. This slows the depletion of adenosine triphosphate (ATP) and also inhibits the degrading processes (phospholipid hydrolysis). Nonetheless, under hypothermic conditions the metabolic rate remains at about 10% and therefore over time, the hypoxic conditions cause substantial injury  this is termed CI injury.
The depletion of ATP due to the inhibition of oxidative metabolism increases levels of adenosine, inosine and hypoxanthine within the cell leading to the formation of lactic acid . This lowers the intracellular pH causing lysosomal instability and the activation of lytic enzymes [14,15]. The depletion of ATP also reduces a large number of cellular processes. Inactivation of the Na+/K+ ATPase pump allows the accumulation of calcium, sodium and water within the cell causing cellular swelling . The binding of transition metals such as iron to their carrier proteins (transferrin, ferritin) is also inhibited which increases the intracellular concentration of free iron [16,17]. This is a strong catalyst for the generation of oxygen free radicals which promotes the production of other free radicals . The impact of CI injury is evident immediately after transplantation when oxygenated blood is re-introduced into the kidney. The downstream effects of ischaemia reperfusion (I/R) injury results in tubular and vascular damage with the impairment of blood flow to the kidney and reduced urine output after transplantation. The kidney can withstand CI times up to 48 hours. Nonetheless, attempts have been made to reduce CI injury and on average the CI time now falls below 24 hours in most transplant centres.
6.1. Delayed graft function
Renal graft function after transplantation is typically measured as incidence of delayed graft function (DGF). There are several definitions of DGF however the majority of centres define DGF as the requirement for dialysis within the first week after transplantation. The diagnosis is based on low urine output, slow decline in serum creatinine levels and increased metabolic instability. Acute tubular injury, otherwise termed acute tubular necrosis (ATN) caused by ischaemic injury is the main cause of DGF after transplantation . DGF is associated with complications such as acute rejection, increased fibrosis and the risk of poorer long term graft survival. It also has a significant economic cost, can complicate patient treatment and prolong hospital stay . Rates of DGF typically range from 5 to 40% in deceased donor kidney transplants . Rates of DGF in live donor transplantation are significantly less (2-5%) due to the short CI time and healthy younger donors .
Many experimental studies have shown that the duration of CI directly influences graft function. Several studies suggest that even after 6 hours of CI, significant injury occurs [22,23]. Clinically, the CI time has been clearly shown as an independent risk factor for DGF and reducing the CI time can reduce the incidence of DGF. In an analysis of a series of DBD transplants the risk of DGF was found to increase by 23% for every 6 hours of CI  and Locke
6.2. Graft survival
The CI time is regarded as an independent risk factor for DGF and DGF is associated with reduced graft survival [27,28]. However, recent evidence suggests that the association of CI time and DGF may have less of an impact on graft survival than previously thought. A multicentre analysis of kidney preservation found that only when the preservation period exceeded 18 hours was the CI time associated with reduced graft survival . A large analysis of registry data of paired deceased donor kidneys found that DGF induced by CI injury had a limited impact on the long term outcome. Nonetheless, in other studies the CI time has been found to independently influence graft survival even in live donor transplantation and in young deceased donors [30,31].
The disparity between DGF and survival is perhaps due to the lack of sensitivity of DGF in determining the severity of kidney injury. DGF is a simple and standard method of reporting early graft dysfunction. However, dialysis within the first week after transplantation can be used to correct metabolic instability without the presence of significant kidney injury. As such, it is difficult to determine the impact of DGF. DGF due to CI can be reversible and therefore have no effect on long term outcome . However, in severe cases, DGF can lead to incomplete recovery and reduced graft survival due to the loss of nephron mass . Giral-Classe
7. Acute rejection
Acute rejection (AR) following renal transplantation can be split into two categories, cell mediated rejection and antibody mediated rejection (also termed vascular rejection). Acute cellular rejection is the more common of the two types and with the introduction of modern immunosuppressive agents rates have dropped from 50% a decade ago to 15-20% today. The typical stimulus for cellular rejection is the presence of so-called ‘passenger leucocytes’ which are immune cells carried within the blood vessels and tissues of the donor organ. Following transplantation they are exposed to the recipient immune system which recognises them as foreign and results in activation of host lymphocytes which attack the donor kidney. Antibody mediated rejection is less common and usually more severe and if left untreated can rapidly destroy the graft.
Acute rejection is an important factor in early outcomes of transplantation and is closely associated with delayed graft function (DGF) [38-41]. The precise link between DGF, acute rejection and CI time is difficult to fully elucidate. Prolonged CI has been shown to be one of the main risk factors for DGF and DGF is an independent risk factor for AR . However, DGF is a result of a number of factors and it is over simplistic to ascribe acute rejection to just one of those factors. Nonetheless there is evidence that the CI time, alongside other factors, including duration of dialysis, number of HLA mismatches, panel reactive antibodies more than 5% are independent predictors of AR. A large retrospective analysis of 611 transplants demonstrated that CI time was the strongest predictor of DGF . The risk of DGF increased from 9.6% with 12 hours CI time to 21.5% with 24 hours CI time. In the same analysis the risk of AR was increased by 4% for each additional hour of CI time and the risk of rejection in patients receiving kidneys with less than 24 hours CI time was 14.1% compared to 29.3% in kidneys with greater than 24 hours CI time. Furthermore, death-censored graft survival is significantly reduced in patients in whom AR complicates DGF. In addition CI duration of greater than 24 hours has a significantly reduced death-censored graft survival in comparison with durations of less than 24 hours .
8. Donor specific effects
Kidneys from DCD and ECD donors commonly present with high rates of DGF compared to SCD and live donors. . DGF typically ranges from 22% to 84% in DCD kidneys compared to 14% to 40% in DBD donors [25, 44-47]. Evidence suggests that the outcome of kidneys from uncontrolled DCDs is poorer when compared to the controlled DCDs with significantly higher rates of DGF, as a response to the longer duration of warm ischaemic (WI) injury under the uncontrolled situation .
Kidneys from ECD have a 70% increased risk of graft loss and higher rates of DGF [25,49,50]. The prognosis is even poorer in DCD kidneys from older donors (over 50 years) with the risk of graft failure rising to 80% .
In addition to DGF, a small but significant proportion of kidneys from DCD donors also have primary non function (PNF) with rates reported to range from 4 to 19% amongst transplant centres over the last 30 years [51,52]. PNF is particularly detrimental as the patient is exposed to surgery and immunosuppressive therapies without benefit. Furthermore, they may become sensitized to donor antigens, reducing the opportunity for future transplants.
The WI insult in DCD kidneys and the reduced capacity of kidneys from ECDs to recover and regenerate are certainly major contributing factors for early graft dysfunction. Experimental evidence suggests that the combined effect of WI and CI injury exacerbates the injury during reperfusion and the duration of CI has been found to have a strong influence on graft outcome . However, the impact of CI in clinical transplantation is again varied. It appears that as in SCDs, long term graft survival is not necessarily affected by DGF and CI not necessarily an independent predictor of graft survival. Recent evidence from clinical DCD and DBD programmes have reported similar rates of graft survival after 5 and 10 years [45,54-57]. In a series of 112 uncontrolled DCD kidneys, DGF rates were 84% compared to 22% in DBD donors . Nevertheless, the graft survival rates were similar in both groups of patients, 69.3% versus 75.5% at 5 years and 50.3% versus 57.9% at 10 years, respectively. The link between WI, CI and graft survival is not well documented. However, it appears that prolonged CI after a period WI may not be as detrimental to graft survival as previously thought and that kidneys can recover from ischaemic injury with no long term effects .
9. Preservation techniques
Organ preservation was first introduced into clinical transplantation in the 1960s. Until this time without proper preservation conditions, kidneys were transplanted as soon as possible after retrieval to minimize the injury. It was then recognized that in order to improve the outcome of transplantation, better methods of preservation were required. Experimental studies in the 1950s by Lapchinsky  in the Soviet Union and the early work by Carrel and Lindbergh, showed that ischaemic injury could be minimized by reducing the temperature . In 1963, Calne
10. Static cold storage
Static cold storage (CS) is undoubtedly the simplest and most widely utilised method of hypothermic preservation. The kidney is flushed with cold preservation solution to remove the blood and cool the organ. The kidney is then stored in solution surrounded by crushed ice. Preservation solutions have been designed to counteract the detrimental effects of CI injury. There are a number of commercially available preservation solution, which all contain the same basic formula. This includes an impermeant to minimise swelling and provide stability to the ultra-structure of the cell. A buffer and a balanced electrolyte composition with either a high or low Na+ / K+ ratio to prevent the build up of intracellular acidosis and further minimize cellular swelling (Table 2). Solutions with a high potassium concentration are classified as intracellular and those with a high sodium concentration extracellular solutions.
|Impermeants||glucose, lactobionate, mannitol, raffinose, sucrose|
|Colloid||hydroxyethyl starch (HES), polyethylene glycol (PEG)|
|Buffers||citrate, histidine, phosphate|
|Electrolytes||calcium, chloride, magnesium, magnesium sulphate, potassium, sodium|
|Anti-oxidants||allopurinol, glutathione, mannitol, trytophan|
|Additives||adenosine, glutamic acid, ketoglutarate|
11. Static cold storage solutions
11.1. Euro Collins
In 1969 Geoffrey Collins developed the first acellular preservation solution (Collins solution) containing a high concentration of potassium and glucose . Collins solution was later modified omitting some of the ingredients such as magnesium, heparin, procain and replacing glucose with mannitol to provide better osmotic properties and lower the viscosity [63-65]
11.2. Hyperosmolar citrate
Hyperosmolar citrate (HOC) or more commonly known as Soltran or Marshall’s solution was first developed in the 1970s as an alternative to Collins solution [66,67]. It is has a high potassium content and contains basic ingredients using citrate as a buffer. Its hypertonicity is designed to prevent fluid entry into cells. It is a relatively inexpensive, non-viscose solution that is still commonly used throughout the UK in kidney transplantation. It is not recommended for DCD or marginal kidneys despite the fact that there is little evidence to support this view.
12. University of Wisconsin solution
University of Wisconsin (UW) solution has a high potassium concentration to maintain the intracellular ionic balance. It is a more complex preservation solution compared to Euro Collin and HOC, containing trisaccharide raffinose and the anion lactobionate as osmotic impermeants, a phosphate buffer, anti-oxidants (glutathione) to scavenge oxygen free radicals, allopurinol to block the activity of xanthine oxidase and adenosine, an ATP precursor. It also contains the colloid hydroxyethyl starch (HES), to prevent cellular swelling . However, it is debatable whether this is it necessary in a static storage solution and there is some evidence showing that HES can increase tubular damage and cause red blood cell aggregation. Another potential disadvantage of UW solution is the high concentrations of potassium. Although thought important in the prevention of the build up of intracellular calcium, potassium can induce cellular depolarization, reduce cellular 5’-triphosphate content and activate voltage-dependent channels, such as calcium channels . Nonetheless, due to its composition UW solution had, and still has, a significant advantage over other preservation solutions enabling kidneys to be stored for longer periods with better function and less histological injury after transplantation. It is still considered the ‘gold standard’ preservation solution today.
13. Histidine-Tryptophan-Ketoglutarate (HTK)
HTK was originally developed as a cardioplegic solution but because of its low viscosity was quickly adopted for clinical preservation of the kidney, pancreas and liver [70-72]. It is an extracellular solution and uses the impermeant mannitol and histidine as a buffer. It also contains 2 amino acids, tryptophan, to stabilize cellular membranes and prevent oxidant damage and ketoglutararate, a substrate to support anaerobic metabolism. Recent concerns have been raised regarding its use for ECD and DCD kidneys or for kidneys with prolonged storage times . Some clinical studies have associated its use with the increased risk of PNF and early graft loss . Nonetheless, it is a popular preservation solution widely used throughout Europe and the UK.
14. Celsior solution
Celsior is an extracellular solution and was initially designed for heart transplantation. It contains a high sodium concentration with histidine as a buffer, lactobionate and mannitol to prevent oedema and glutathione as an antioxidant. The solution has proved beneficial in heart, liver, pancreas and in kidney transplantation [75-78].
An abundance of experimental studies have investigated the efficacy of one solution over another with the majority of studies labelling UW solution as the most superior. However, clinically the evidence is sparse. UW, HTK and Celsior appear to be the better preservation solutions with little difference in rates of DGF between the solutions its usage. Euro Collin solution is not widely used and is regarded as inferior with the suggestion of increasing the risk of DGF . The outcome of individual preservation solutions is more apparent when the CI time is extended beyond 24 hours with UW fairing significantly better than other solutions.
16. Hypothermic machine perfusion
Since the introduction of CS techniques in the 1970s there has been much debate about whether CS or hypothermic machine perfusion (HMP) is the best method of kidney preservation. Undoubtedly, the simplicity of CS has a significant advantage over HMP. However, HMP is it thought to be a better method of preservation in that it allows a continual flush of the microcirculation, prevents the accumulation of waste products, sustains a higher metabolic rate, protects against depolarization of the endothelial cell membrane and reduces free radical formation .
Folkert O Belzer was the first to develop a portable HMP system [81,82] in the 1960s. However, with the introduction and success of CS in the 1970s there was little development of this technique in subsequent decades. Nonetheless, with the increasing use of DCD and ECD kidneys over the last decade, there has been renewed interest into the use of HMP. New simpler and portable systems have been developed such as the Lifeport Kidney Transporter (Organ Recovery System, US) which has encouraged the use of this technology. Many experimental studies have found HMP to improve preservation [7,12] and the quality of the kidney. The largest multicentre clinical trial conducted in Europe comparing CS and HMP in deceased donors found that HMP reduced the risk of DGF compared to CS (adjusted odds ratio, 0.57; P=0.01] and improved 1 and 3 year graft survival [83,84]. Although the overall rate of DGF was only reduced by 6%.
The evidence suggests that HMP may be more beneficial in reducing DGF rates in marginal kidneys. In a sub-analysis of 82 pairs of DCD kidneys from the European trial, the DGF rate in the HMP group was 53.7% compared to 69.5% in kidneys that were statically stored . However, there was no significant difference in graft survival at 1 or 3 years. In a further sub-analysis of ECD donors in this trial, HMP reduced rates of DGF from 29.7% to 22% and also improved 1 and 3 year graft survival in ECD kidneys [84,86]. In contrast to this support for HMP, a multicentre UK trial found no beneficial effects of HMP. 45 pairs of controlled DCD kidneys were randomized to HMP or CS . The DGF rates were 58% vs 56% in the HMP and CS groups respectively. However, this trial has been criticised for the sequential design and the small number of patients .
HMP techniques are still open to criticism with the suggestion of increased endothelial injury, as found in a recent study of porcine livers , risk of trauma to the vessels and the question of cost effectiveness compared to static storage techniques . Nonetheless, it appears that HMP may hold a significant advantage in reducing CI injury compared to CS techniques. The experimental evidence is strong and there is a growing abundance of evidence from clinical studies to suggest an advantage. However, the evidence is not conclusive and there is a need for more clinical trials to determine the superior method of preservation.
17. Normothermic machine perfusion
Maintaining an organ under normothermic conditions is an alternative technique of preservation. Continuous perfusion of the kidney at warmer temperatures with the delivery of nutrients and oxygen has the advantage of avoiding hypothermic injury and hypoxia. In addition, it also may aid recovery and prevent further injury.
Early attempts at normothermic preservation were generally unsuccessful due to the inability to maintain cellular integrity and support renal metabolism. However, advances have been made over the last few decades with the use of technology borrowed from cardiac surgery. The development of less traumatic perfusion pumps and the recognition of the necessity for the delivery of nutrients and oxygen to achieve successful perfusion has made normothermic preservation a realistic contender in clinical transplantation.
Normothermic perfusion can be applied in various ways. The concept of extracorporeal membrane oxygenation (ECMO) to maintain extracorporeal circulation at normal room or body temperature with hyperoxygenated blood can be used to maintain tissue perfusion after the heart has stopped. Normothermic recirculation has proved beneficial in the retrieval of hearts, lungs and abdominal organs. Valero
In consideration of the logistical problems of prolonged preservation a great deal of research has focused on using normothermic preservation in combination with hypothermic techniques. Experimentally, intermediate periods of normothermic preservation have been used to restored energy metabolism with replenishment of adenosine levels, effectively ‘resuscitating’ the organ and retaining viability compared to kidneys stored under hypothermic conditions [96,97].
Measuring the amount of ischaemic injury during preservation would be advantageous as the quality of the kidney could be assessed and a decision made upon its viability. This would be particularly beneficial for marginal kidneys to reduce the likelihood of PNF. Viability is normally assessed by numerous factors including donor history, duration of cardiac arrest, the quality of in-situ perfusion, CI interval and visual inspection of the kidney. Ultimately this relies on the judgement of an experienced surgeon. To avoid PNF, surgeons are typically cautious and therefore many kidneys are deemed unsuitable for transplantation and are discarded . HMP has been used to assess viability. Two aspects can be measured; Firstly, the continuous recirculation of preservation solution through the kidney allows the perfusate flow to be measured and intra-renal resistance can be calculated. Secondly, the perfusate can be sampled to measure cellular injury.
Clinically, the perfusion flow index (PFI) has been used as a measure of flow and resistance [103,104]. This is based on a minimum flow being obtained for a given pressure. The Transplant Group at Newcastle, UK recommend that a PFI of greater than 0.6ml/min/mmHg/100 gram of kidney is needed for a kidney to be deemed suitable for transplantation . However, the ability of these parameters to predict DGF or PNF in clinical practice is limited. Jochman
Viability can also be measured by sampling the perfusate for biomarkers of cellular injury. Markers such as redox free iron, glutathione S-transferase (GST), total glutathione S-transferase (tGST), lactate dehydrogenase (LDH), N-acetyl-β-D-glucosaminidase (NAG), heart-type fatty acid binding protein (H-FABP) and alanine aminopeptidase (Ala-AP) have all been used to determine injury [104-106,109]. There is little information on their predictive value. However, Jochman
Normothermic preservation techniques may hold more promise in the assessment of viability compared to HMP techniques. During normothermic perfusion renal function and metabolism are restored. In experimental models, low levels of blood flow, reduced renal function and low oxygen consumption have been associated with increased ischaemic injury. Furthermore, these functional measures could be combined with injury biomarkers to assess the quality of the kidney.
19. Experimental studies
There is a growing body of evidence in support of recovering ischaemically damaged organs with oxygenated preservation techniques at low temperatures. Historically, oxygenation was considered an essential component of hypothermic kidney preservation in order to support mitochondrial resynthesis of ATP and to delay the injury process. However, with the introduction of the modern day preservation solutions, and the rapid adoption of simple CS techniques, oxygen was not thought to be a vital ingredient and as such is not commonly applied in the clinical setting. Various techniques have been used to apply oxygen under CS and HMP conditions.
Retrograde oxygen persufflation is a simple technique whereby filtered and humidified oxygen is bubbled directly through the renal vasculature during CS. The gas is then allowed to escape through small perforations in the surface of the organ. Reports of its application date back to the 1970s [110,111]. Experimentally, there has been renewed interest in this technique showing a beneficial effect on graft function when compared to CS and HMP techniques [112,113].
Hyperbaric oxygenation is the delivery of oxygen under increased atmospheric pressure. Hyperbaric oxygenation is normally used to treat decompression sickness, carbon monoxide poisoning, gas embolism, circulatory disorders and to promote wound healing [114-116]. However, it has been used in organ preservation. Under normal atmospheric pressure there is a limit to the amount of oxygen that can be carried in the blood. Increasing the atmospheric pressure at which it is delivered, increases the amount of dissolved oxygen in the plasma allowing deeper penetration into the tissue (Henry’s Law). Therefore, tissues can be adequately oxygenated in the absence of a blood flow, a particular advantage in organ preservation [114,115]. Although an interesting concept and benefits have been demonstrated in liver and bowel transplantation, there has been little evidence of its use in kidney preservation in recent times.
Oxygen can also be added during HMP. At present, HMP is not supplemented with oxygen based on the presumption that air equilibration in perfusates sufficiently supports energy metabolism and that oxygen consumption at 4ºC is around 5% of that found at body temperature . However, ATP can be restored in part, with the addition of oxygen and energy substrates during perfusion . Short periods of oxygenated perfusion after CS have also been used to resuscitate and condition organs, correcting ATP loss, reducing levels of oxidative stress and improving organ viability . The addition of free radial scavengers such as superoxide dismutase (SOD) to the preservation solution has been found to be beneficial [119,120] in preventing the generation of oxygen free radicals in this highly oxygenated environment.
20. Oxygenated solutions
Oxygen can also be effectively administered during preservation by the use of artificial oxygen carriers. Perfluorocarbons (PFC) are inert solutions that have a high capacity for dissolving oxygen. They release oxygen down a concentration gradient creating a highly oxygenated environment which is not affected by temperature [121,122]. They can be added simply during CS in a technique called the two layer method (TLM). The density of the PFC allows two layers to be formed, PFC on the bottom and the preservation solution on top. The organ is placed in the solution and remains between the two layers. Oxygen can be continuously added allowing adequate diffusion through the organ. TLM has been particularly beneficial for pancreas preservation, allowing a sufficient amount of ATP to be generated to improve organ viability [121,123]. The use of TLM has shown potential in other organs but has failed to gain much support as the ability of oxygen to penetrate deep into tissue in more densely capsulated organs has been questioned. In the kidney its beneficial effect was found in a rat model, however, when applied in a porcine model the results showed no advantage [121,124-126].
PFC can also be formulated as an emulsion for continuous perfusion and was applied during early attempts at machine perfusion [126-129]. However, the instability and adverse effects of the emulsions at that time prevented their continued application .
Other novel oxygen carriers have recently been applied experimentally in kidney preservation. Hemarina-M101 (M101] is a respiratory pigment derived from a marine invertebrate,
In addition to hypothermic conditions, perfluorochemical and haemoglobin solutions can also be used to deliver oxygen at normothermic temperatures . Brasile
Historically, haemoglobin based solutions such as Stroma-free haemoglobin failed to demonstrate benefit experimentally because of toxic effects on the kidney. However, a newly developed solution, pyridoxalated haemoglobin-polyoxyethylene (PHP) has been deemed to be a more stable solution . New more stable 2nd and 3rd generation PFCs are being developed and several are undergoing clinical trials to assess their safety. Humphreys
Other solutions such as Lifor, a new artificial preservation medium containing a non protein oxygen carrier that can be used at room temperature may also be used for preservation [136, 137]. These new solutions may hold more promise for future development of normothermic preservation perfusates. Nonetheless, the use of these normothermic perfusates in clinical practice is still awaited.
21. Experimental agents
I/R injury involves a cascade of events centralised by activated endothelial cells immediately after transplantation. One of the first inflammatory responses is the infiltration of neutrophils into the tissue. Cell adhesion molecules are recognised by leukocytes which interact with tissue cells to allow the movement of immune cells and mediators to the injury site [138,139]. This is mainly mediated through the up-regulation of endothelial adhesion molecules (ICAM-1, VCAM-1 and E-Selectin) . The release of pro-inflammatory cytokines and chemokines, activation of the complement system and production of reactive oxygen species (ROS)  also cause significant cellular injury.
A vast number of therapies have been investigated to ameliorate the detrimental effects of I/R injury such as vasodilatory agents [140,141], antioxidants [142-144], anti-inflammatory agents [145,146] and growth factors  and in the experimental setting many of these have proved beneficial. Of particular interest are the therapies that collectively target several mechanisms of I/R injury, these include the endogenous gaseous molecules nitric oxide (NO) [148,149], carbon monoxide (CO) [150,151] and hydrogen sulphide (H2S) [152,153]. Experimental models have shown their ability to reduce inflammation, oxidative damage, apoptosis and promote smooth muscle relaxation causing vasodilation to enhance renal blood flow. However, their application into clinical practice is awaited.
There is no single agent used as standard clinical practice to treat I/R injury and reduce DGF. Nonetheless, there are several agents of interest that have recently been examined in clinical trials. Recombinant human erythropoietin (EPO) is a treatment for anaemia in renal patients however it also has cytoprotective properties and has been shown to protect against kidney injury in experimental models [154, 155]. However, the results from two clinical trials contradict the majority of animal studies and showed no benefit of EPO in reducing rates of DGF [156,157]. Furthermore, in one trial concerns of the increase in the incidence of graft thrombosis where raised . Other trials to assess the effects of EPO are ongoing and the results are pending. It has been suggested that EPO mediates protection through a tissue receptor that is distinct from the classical EPO‐receptor that is known to mediate erythropoiesis . A new compound has been formulated, pyroglutamate helix B surface peptide (pHBSP) that has the tissue‐protective properties similar to those of EPO but without causing erythropoiesis . Early experimental models suggest that this agent is beneficial in reducing kidney injury and may hold promise for future clinical trials.
Several volatile anaesthetic agents sevoflurane and desflurane are also being trialled in clinical transplantation to reduce kidney injury. These agents are thought to have a conditioning effect that up-regulates protective mechanisms to reduce the I/R injury response . The conditioning effect can also be applied by short intervals of ischaemia either directly to the organ or remotely to a limb . It can be applied to the donor or recipient and again experimental models have shown the benefits of conditioning techniques. They are particularly attractive for clinical transplantation in that no pharmacological intervention is required and therefore the technique is expected to have a high safety profile. The results of several clinical trials are eagerly awaited. Propofol is another anaesthetic agent that may reduce I/R injury [161,162]. Experimental models have highlighted the anti-oxidant and anti-apoptotic properties of the agent [161,162].
There has been a great deal of emphasis on stem cell therapy to reduce kidney injury. The ability of stem cells to differentiate into multiple lineages with the capacity to stimulate the regeneration of renal tissue is particularly attractive in kidney transplantation. Bone marrow derived mesenchymal stem cells have been used in the rat kidney to reduce inflammation and oxidative damage [163-165]. However, there has been no clinical application of this therapy in kidney transplantation.
Immunosuppressant therapies used on induction can be used to reduce I/R injury and DGF. They suppress leukocyte infiltration and reduce endothelial injury. Anti-CD25  and antithymocyte globulin (ATG)  are amongst some of the agents being currently being studied to reduce the incidence of DGF.
CI injury is detrimental to early graft function and as such early graft dysfunction is associated with reduced graft survival and complications after transplantation. However, the direct impact of CI on long term graft survival is less clear. Clinical studies suggest that CI may not necessarily be an independent risk factor for reduced graft survival. Nonetheless, further evidence is needed to examine the relationship between CI injury and graft survival. Hypothermic preservation techniques are designed to counteract the detrimental effect of CI injury and hypothermic machine perfusion is emerging as a superior method of preservation compared with static cold storage. Other preservation techniques are being developed such as normothermic perfusion and the addition of oxygen and oxygen carriers during hypothermic preservation. These techniques may hold promise for the future to limit the damage caused by CI injury. Therapeutic agents administered to the recipient may also prove beneficial in reducing early graft dysfunction. Nonetheless, translation of these therapies from animal models to clinical practice remains difficult and the search for the optimal agent or therapy is ongoing.
Rao P. S Schaubel D. E Wei G Fenton S. S Evaluating the survival benefit of kidney retransplantation. 2006Sep 15; 82 5 669 674
Impact of renal cadaveric transplantation on survival in end-stage renal failure: evidence for reduced mortality risk compared with hemodialysis during long-term follow-up. J Am Soc Nephrol Schnuelle P Lorenz D Trede M Van Der Woude F. J 1998Nov; 9 11 2135 2141
Wolfe R. A Ashby V. B Milford E. L Ojo A. O Ettenger R. E Agodoa L. Y et al Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant.N Engl J Med 1999Dec 2; 341 23 1725 1730
Daemen J. W Oomen A. P Kelders W. P Kootstra G The potential pool of non-heart-beating kidney donors.Clin Transplant 1997Apr; 11 2 149 154
del Barrio R, Arias J, Ruiz F, Iglesias J, de Elias R, et al. Alvarez J Non-heart-beating donors from the streets: an increasing donor pool source. 2000Jul 27; 70 2 314 317
Nyberg G Nilsson B Norden G Karlberg I Outcome of renal transplantation in patients over the age of 60: a case-control study.Nephrol Dial Transplant 1995 10 1 91 94
Taylor M. J Baicu S. C Current state of hypothermic machine perfusion preservation of organs: The clinical perspective 2010Jul;60(3 Suppl):S 20 35
Terasaki P. I Cho Y. W Cecka J. M Strategy for eliminating the kidney shortage.Clin Transpl 1997 1997 265 267
Kootstra G Daemen J. H Oomen A. P Categories of non-heart-beating donors.Transplant Proc 1995Oct; 27 5 2893 2894
van den Akker L, Welten RJ, Schurink GW, et al. In situ preservation of kidneys from donors after cardiac death: results and complications. Ann Surg Snoeijs M. G Dekkers A. J Buurman W. A 2007Nov; 246 5 844 852
MacMillan-Crow LA. Mitchell T Saba H Laakman J Parajuli N Role of mitochondrial-derived oxidants in renal tubular cell cold-storage injuryFree Radic Biol Med 2010Nov 1; 49 8 1273 1282
Hypothermic perfusion preservation: the future of organ preservation revisited? Cryobiology Fuller B. J Lee C. Y 2007Apr; 54 2 129 145
Kosieradzki M Rowinski W Ischemia/reperfusion injury in kidney transplantation: mechanisms and preventionTransplant Proc 2008Dec; 40 10 3279 3288
Salahudeen A. K Cold ischemic injury of transplanted kidneys: new insights from experimental studies.Am J Physiol Renal Physiol 2004Aug;287(2):F 181 7
Weinberg J. M The cell biology of ischemic renal injury.Kidney Int 1991Mar; 39 3 476 500
Carden D. L Granger D. N Pathophysiology of ischaemia-reperfusion injury.J Pathol 2000Feb; 190 3 255 266
Cold-induced injury to lung epithelial cells can be inhibited by iron chelators- implications for lung preservation. Eur J Cardiothorac Surg Pizanis N Gillner S Kamler M De Groot H Jakob H Rauen U 2011Oct; 40 4 948 955
Kwiatkowski A Wszola M Perkowska-ptasinska A Ostrowski K Domagala P Fesolowicz S et al Influence of preservation method on histopathological lesions of kidney allograftsAnn Transplant 2009Jan-Mar; 14 1 10 13
Andrew Bradley J, Andrews PA, Koffman G, et al. Brook N. R Waller J. R Richardson A. C A report on the activity and clinical outcomes of renal non-heart beating donor transplantation in the United Kingdom.Clin Transplant 2004Dec; 18 6 627 633
Jr, Poggio ED, Parikh CR. Yarlagadda S. G Coca S. G Formica R. N Association between delayed graft function and allograft and patient survival: a systematic review and meta-analysisNephrol Dial Transplant 2009Mar; 24 3 1039 1047
Gok M. A Shenton B. K Pelsers M Whitwood A Mantle D Cornell C et al Reperfusion injury in renal transplantation: comparison of LD, HBD and NHBD renal transplants.Ann Transplant 2004 9 2 33 34
Dragun D Hoff U Park J. K Qun Y Schneider W Luft F. C et al Prolonged cold preservation augments vascular injury independent of renal transplant immunogenicity and function.Kidney Int 2001Sep; 60 3 1173 1181
Wilhelm S. M Simonson M. S Robinson A. V Stowe N. T Schulak J. A Cold ischemia induces endothelin gene upregulation in the preserved kidney.J Surg Res 1999Jul; 85 1 101 108
Ojo A. O Wolfe R. A Held P. J Port F. K Schmouder R. L Delayed graft function: risk factors and implications for renal allograft survival. 1997Apr 15; 63 7 968 974
7 7 1797 1807 Locke JE, Segev DL, Warren DS, Dominici F, Simpkins CE, Montgomery RA. Outcomes of kidneys from donors after cardiac death: implications for allocation and preservation. Am J Transplant 2007 Jul;7(7):1797-1807
Kayler L. K Srinivas T. R Schold J. D Influence of CIT-induced DGF on kidney transplant outcomes.Am J Transplant 2011Dec; 11 12 2657 2664
Dittrich S Groneberg D. A Von Loeper J Lippek F Hegemann O Grosse-siestrup C et al Influence of cold storage on renal ischemia reperfusion injury after non-heart-beating donor explantationNephron Exp Nephrol 2004e 97 102
Siedlecki A Irish W Brennan D. C Delayed graft function in the kidney transplant.Am J Transplant 2011Nov; 11 11 2279 2296
Opelz G Dohler B Multicenter analysis of kidney preservation. 2007Feb 15; 83 3 247 253
Cold ischemia time and allograft outcomes in live donor renal transplantation: is live donor organ transport feasible? Am J Transplant Simpkins C. E Montgomery R. A Hawxby A. M Locke J. E Gentry S. E Warren D. S et al 2007Jan; 7 1 99 107
Impact of cold ischemia time on renal allograft outcome using kidneys from young donors. Transpl Int Hernandez D Estupinan S Perez G Rufino M Gonzalez-posada J. M Luis D et al 2008Oct; 21 10 955 962
Is kidney injury a reversible process? Curr Opin Nephrol Hypertens Chatziantoniou C Dussaule J. C 2008Jan; 17 1 76 81
Barrientos A Portoles J Herrero J. A Torralbo A Prats D Gutierrez-millet V et al Glomerular hyperfiltration as a nonimmunologic mechanism of progression of chronic renal rejection. 1994Mar 15; 57 5 753 756
Giral-classe M Hourmant M Cantarovich D Dantal J Blancho G Daguin P et al Delayed graft function of more than six days strongly decreases long-term survival of transplanted kidneysKidney Int 1998Sep; 54 3 972 978
Parikh C. R Jani A Mishra J Ma Q Kelly C Barasch J et al Urine NGAL and IL-18 are predictive biomarkers for delayed graft function following kidney transplantation.Am J Transplant 2006Jul; 6 7 1639 1645
Hall I. E Yarlagadda S. G Coca S. G Wang Z Doshi M Devarajan P et al IL-18 and urinary NGAL predict dialysis and graft recovery after kidney transplantationJ Am Soc Nephrol 2010Jan; 21 1 189 197
Koyner J. L Vaidya V. S Bennett M. R Ma Q Worcester E Akhter S. A et al Urinary biomarkers in the clinical prognosis and early detection of acute kidney injuryClin J Am Soc Nephrol 2010Dec; 5 12 2154 2165
Mclaren A. J Jassem W Gray D. W Fuggle S. V Welsh K. I Morris P. J Delayed graft function: risk factors and the relative effects of early function and acute rejection on long-term survival in cadaveric renal transplantationClin Transplant 1999Jun; 13 3 266 272
Lebranchu Y Halimi J. M Bock A Chapman J Dussol B Fritsche L et al Delayed graft function: risk factors, consequences and parameters affecting outcome-results from MOST, A Multinational Observational Study.Transplant Proc 2005Jan-Feb; 37 1 345 347
Rosenthal J. T Danovitch G. M Wilkinson A Ettenger R. B The high cost of delayed graft function in cadaveric renal transplantation. 1991May; 51 5 1115 1118
Sanfilippo F Vaughn W. K Spees E. K Lucas B. A The detrimental effects of delayed graft function in cadaver donor renal transplantation. 1984Dec; 38 6 643 648
Mikhalski D Wissing K. M Ghisdal L Broeders N Touly M Hoang A. D et al Cold ischemia is a major determinant of acute rejection and renal graft survival in the modern era of immunosuppression.Transplantation 2008Apr 15;85(7 Suppl):S 3 9
Nicholson M. L Metcalfe M. S White S. A Waller J. R Doughman T. M Horsburgh T et al A comparison of the results of renal transplantation from non-heart-beating, conventional cadaveric, and living donors. Kidney Int 2000Dec; 58 6 2585 2591
Gagandeep S Matsuoka L Mateo R Cho Y. W Genyk Y Sher L et al Expanding the donor kidney pool: utility of renal allografts procured in a setting of uncontrolled cardiac death.Am J Transplant 2006Jul; 6 7 1682 1688
DL, et al. D Alessandro A. M Fernandez L. A Chin L. T Shames B. D Turgeon N. A Scott Donation after cardiac death: the University of Wisconsin experience.Ann Transplant 2004 9 1 68 71
Whiting J. F Delmonico F Morrissey P Basadonna G Johnson S Lewis W. D et al Clinical results of an organ procurement organization effort to increase utilization of donors after cardiac death. 2006May 27; 81 10 1368 1371
Tojimbara T Fuchinoue S Iwadoh K Koyama I Sannomiya A Kato Y et al Improved outcomes of renal transplantation from cardiac death donors: a 30-year single center experienceAm J Transplant 2007Mar; 7 3 609 617
Summers D. M Johnson R. J Allen J Fuggle S. V Collett D Watson C. J et al Analysis of factors that affect outcome after transplantation of kidneys donated after cardiac death in the UK: a cohort studyLancet 2010Oct 16; 376 9749 1303 1311
Sung R. S Guidinger M. K Christensen L. L Ashby V. B Merion R. M Leichtman A. B et al Development and current status of ECD kidney transplantationClin Transpl 2005 2005 37 55
Saidi R. F Elias N Kawai T Hertl M Farrell M. L Goes N et al Outcome of kidney transplantation using expanded criteria donors and donation after cardiac death kidneys: realities and costsAm J Transplant 2007Dec; 7 12 2769 2774
Results of transplantation with kidneys from non-heart-beating donors. Transplant Proc Hordijk W Hoitsma A. J Van Der Vliet J. A Hilbrands L. B 2001Feb-Mar;33(1-2):1127-1128.
Daemen J. H De Vries B Oomen A. P Demeester J Kootstra G Effect of machine perfusion preservation on delayed graft function in non-heart-beating donor kidneys--early results.Transpl Int 1997 10 4 317 322
JL, et al. Johnson R. J Fuggle S. V O Neill J Start S Bradley J. A Forsythe Factors influencing outcome after deceased heart beating donor kidney transplantation in the United Kingdom: an evidence base for a new national kidney allocation policy 2010Feb 27; 89 4 379 386
Barlow A. D Metcalfe M. S Johari Y Elwell R Veitch P. S Nicholson M. L Case-matched comparison of long-term results of non-heart beating and heart-beating donor renal transplantsBr J Surg 2009Jun; 96 6 685 691
Singh R. P Farney A. C Rogers J Zuckerman J Reeves-daniel A Hartmann E et al Kidney transplantation from donation after cardiac death donors: lack of impact of delayed graft function on post-transplant outcomes.Clin Transplant 2011Mar-Apr; 25 2 255 264
Snoeijs M. G Schaubel D. E Hene R Hoitsma A. J Idu M. M Ijzermans J. N et al Kidneys from donors after cardiac death provide survival benefitJ Am Soc Nephrol 2010Jun; 21 6 1015 1021
Hoogland E. R Snoeijs M. G Winkens B Christaans M. H Van Heurn L. W Kidney Transplantation from Donors after Cardiac Death: Uncontrolled versus Controlled DonationAm J Transplant 2011Jul; 11 7 1427 1434
Taylor C. J Kosmoliaptsis V Sharples L. D Prezzi D Morgan C. H Key T et al Ten-year experience of selective omission of the pretransplant crossmatch test in deceased donor kidney transplantation 2010Jan 27; 89 2 185 193
Lapchinsky A. G Recent results of experimental transplantation of preserved limbs and kidneys and possible use of this technique in clinical practice.Ann N Y Acad Sci 1960May 31; 87 539 571
Carrel A Lindbergh C. A The Culture of Whole Organs.Science 1935Jun 21; 81 2112 621 623
Calne R. Y Pegg D. E Pryse-davies J Brown F. L Renal Preservation by Ice-Cooling: an Experimental Study Relating to Kidney Transplantation from Cadavers.Br Med J 1963Sep 14; 2 5358 651 655
Collins G. M Bravo-shugarman M Terasaki P. I Kidney preservation for transportationInitial perfusion and 30 hours’ ice storage. Lancet 1969Dec 6; 2 7632 1219 1222
Opelz G Terasaki P. I Kidney preservation: perfusion versus cold storage-1975.Transplant Proc 1976Mar; 8 1 121 125
Collins G. M Halasz N. A Current aspects of renal preservation. 1977Jul;10(1 Suppl): 22 32
Collins G. M Halasz N. A Simplified 72-hr kidney storage.Surg Forum 1974 25 0 275 277
Slapak M Wilson A Clyne C Bagshaw H Naik R. B Lee H. A Hyperosmolar citrate versus perfudex: a functional comparison in clinical kidney preservation.Transplant Proc 1979Mar; 11 1 478 481
Jablonski P Howden B Marshall V Scott D Evaluation of citrate flushing solution using the isolated perfused rat kidney. 1980Oct; 30 4 239 243
Belzer F. O Glass N. R Sollinger H. W Hoffmann R. M Southard J. H A new perfusate for kidney preservation. 1982Mar; 33 3 322 323
Hadj Aissa Hauet T Han Z Doucet C Ramella-virieux S A, Carretier M, et al. A modified University of Wisconsin preservation solution with high-Na+ low-K+ content reduces reperfusion injury of the pig kidney graft. 2003Jul 15; 76 1 18 27
Groenewoud A. F Isemer F. E Stadler J Heideche C. D Florack G Hoelscher M A comparison of early function between kidney grafts protected with HTK solution versus Euro-Collins solution.Transplant Proc 1989Feb;21(1 Pt 2): 1243 EOF 4 EOF
Minor T Olschewski P Tolba R. H Akbar S Kocalkova M Dombrowski F Liver preservation with HTK: salutary effect of hypothermic aerobiosis by either gaseous oxygen or machine perfusionClin Transplant 2002Jun; 16 3 206 211
. Clinical experience with histidine-tryptophan-ketoglutarate solution in abdominal organ preservation: a review of recent literature. Clin Transplant , Fridell JA , Mangus RS Tector AJ 2009Jun-Jul; 23 3 305 312.
Lynch R. J Kubus J Chenault R. H Pelletier S. J Campbell D. A Englesbe M. J Comparison of histidine-tryptophan-ketoglutarate and University of Wisconsin preservation in renal transplantationAm J Transplant 2008Mar; 8 3 567 573
Stevens R. B Skorupa J. Y Rigley T. H Yannam G. R Nielsen K. J Schriner M. E et al Increased primary non-function in transplanted deceased-donor kidneys flushed with histidine-tryptophan-ketoglutarate solutionAm J Transplant 2009May; 9 5 1055 1062
Boku N Tanoue Y Kajihara N Eto M Masuda M Morita S A comparative study of cardiac preservation with Celsior or University of Wisconsin solution with or without prior administration of cardioplegiaJ Heart Lung Transplant 2006Feb; 25 2 219 225
Boudjema K Grandadam S Compagnon P Salame E Wolf P Ducerf C et al Efficacy and safety of Celsior preservation fluid in liver transplantation: one-year follow up of a prospective, multicenter, non-randomized study.Clin Transplant 2011Apr 21.
Fridell J. A Mangus R. S Powelson J. A Organ preservation solutions for whole organ pancreas transplantationCurr Opin Organ Transplant 2010Dec 9.
Nunes P Mota A Figueiredo A Macario F Rolo F Dias V et al Efficacy of renal preservation: comparative study of Celsior and University of Wisconsin solutionsTransplant Proc 2007Oct; 39 8 2478 2479
PJ. O Callaghan J. M Knight S. R Morgan R. D Morris Preservation solutions for static cold storage of kidney allografts: a systematic review and meta-analysis.Am J Transplant 2012Apr; 12 4 896 906
Vaziri N Thuillier R Favreau F. D Eugene M Milin S Chatauret N. P et al Analysis of machine perfusion benefits in kidney grafts: a preclinical studyJ Transl Med 2011Jan 25;9:15.
Belzer F. O Ashby B. S Dunphy J. E 24-Hour and 72-Hour Preservation of Canine Kidneys. 1967Sep 9; 2 7515 536 538
Belzer F. O Current methods of kidney storage. 1969May-Jun; 5 6 444 446
Moers C Smits J. M Maathuis M. H Treckmann J Van Gelder F Napieralski B. P et al Machine perfusion or cold storage in deceased-donor kidney transplantationN Engl J Med 2009Jan 1; 360 1 7 19
Machine Preservation Trial Study Group. Machine perfusion or cold storage in deceased-donor kidney transplantation. N Engl J Med Moers C Pirenne J Paul A Ploeg R. J 2012Feb 23; 366 8 770 771
Jochmans I Moers C Smits J. M Leuvenink H. G Treckmann J Paul A et al Machine perfusion versus cold storage for the preservation of kidneys donated after cardiac death: a multicenter, randomized, controlled trial. Ann Surg 2010Nov; 252 5 756 764
Treckmann J Moers C Smits J. M Gallinat A Maathuis M. H Van Kasterop-kutz M et al Machine perfusion versus cold storage for preservation of kidneys from expanded criteria donors after brain death.Transpl Int 2011Jun; 24 6 548 554
Watson C. J Wells A. C Roberts R. J Akoh J. A Friend P. J Akyol M et al Cold machine perfusion versus static cold storage of kidneys donated after cardiac death: a UK multicenter randomized controlled trial.Am J Transplant 2010Sep; 10 9 1991 1999
Jochmans I Moers C Ploeg R Pirenne J To perfuse or not to perfuse kidneys donated after cardiac deathAm J Transplant 2011Feb; 11 2 409 410
Hypothermic machine perfusion of the liver: is it more complex than for the kidney? Transplant Proc Monbaliu D Heedfeld V Liu Q Wylin T Van Pelt J Vekemans K et al 2011Nov; 43 9 3445 3450
Bond M Pitt M Akoh J Moxham T Hoyle M Anderson R The effectiveness and cost-effectiveness of methods of storing donated kidneys from deceased donors: a systematic review and economic model.Health Technol Assess 2009Aug;13(38):iii-iv, xi-xiv, 1 156
Valero R Cabrer C Oppenheimer F Trias E Sanchez-ibanez J De Cabo F. M et al Normothermic recirculation reduces primary graft dysfunction of kidneys obtained from non-heart-beating donors.Transpl Int 2000 13 4 303 310
nd, Magee JC, Rudich S, Maraschio M, et al. Gravel M. T Arenas J. D Chenault R Kidney transplantation from organ donors following cardiopulmonary death using extracorporeal membrane oxygenation support.Ann Transplant 2004 9 1 57 58
Lee C. Y Tsai M. K Ko W. J Chang C. J Hu R. H Chueh S. C et al Expanding the donor pool: use of renal transplants from non-heart-beating donors supported with extracorporeal membrane oxygenationClin Transplant 2005Jun; 19 3 383 390
Reznik O Bagnenko S Skvortsov A Ananyev A Senchik K Loginov I et al Rehabilitation of ischemically damaged human kidneys by normothermic extracorporal hemoperfusion in situ with oxygenation and leukocyte depletionTransplant Proc 2010Jun; 42 5 1536 1538
Reznik O Bagnenko S Scvortsov A Loginov I Ananyev A Senchik K et al The use of in-situ normothermic extracorporeal perfusion and leukocyte depletion for resuscitation of human donor kidneys 2010Sep; 25 5 343 348
Intermediate normothermic perfusion during cold storage of ischemically injured kidneys. Transplant Proc Maessen J. G Van Der Vusse G. J Vork M Kootstra G 1989Feb;21(1 Pt 2):1252-1253.
The beneficial effect of intermediate normothermic perfusion during cold storage of ischemically injured kidneys. A study of renal nucleotide homeostasis during hypothermia in the dog. Transplantation Maessen J. G Van Der Vusse G. J Vork M Kootstra G 1989Mar; 47 3 409 414
Brasile L Stubenitsky B. M Booster M. H Arenada D Haisch C Kootstra G Transfection and transgene expression in a human kidney during ex vivo warm perfusion.Transplant Proc 2002Nov;34(7): 2624 EOF
Hypothermia--a limiting factor in using warm ischemically damaged kidneys. Am J Transplant Brasile L Stubenitsky B. M Booster M. H Arenada D Haisch C Kootstra G 2001Nov; 1 4 316 320
Brasile L Stubenitsky B. M Booster M. H Lindell S Araneda D Buck C et al Overcoming severe renal ischemia: the role of ex vivo warm perfusion. 2002Mar 27; 73 6 897 901
Brasile L Stubenitsky B. M Booster M. H Haisch C Kootstra G NOS: the underlying mechanism preserving vascular integrity and during ex vivo warm kidney perfusionAm J Transplant 2003Jun; 3 6 674 679
Hosgood S. A Nicholson M. L First in Man Renal Transplantation After Ex Vivo Normothermic Perfusion.Transplantation 2011Aug 11.
Asher J Wilson C Gok M Shenton B. K Stamp S Wong Y. T et al Transplantation from non heart beating donors in Newcastle upon Tyne.Ann Transplant 2004 9 1 59 61
Do tissue damage biomarkers used to assess machine-perfused NHBD kidneys predict long-term renal function post-transplant? Clin Chim Acta Gok M. A Pelzers M Glatz J. F Shenton B. K Buckley P. E Peaston R et al 2003Dec;338(1-2):33-43.
Gok M. A Pelsers M Glatz J. F Shenton B. K Peaston R Cornell C et al Use of two biomarkers of renal ischemia to assess machine-perfused non-heart-beating donor kidneys.Clin Chem 2003Jan; 49 1 172 175
Graft quality assessment in kidney transplantation: not an exact science yet! Curr Opin Organ Transplant Jochmans I Pirenne J 2011Apr; 16 2 174 179
Sonnenday C. J Cooper M Kraus E Gage F Handley C Montgomery R. A The hazards of basing acceptance of cadaveric renal allografts on pulsatile perfusion parameters alone. 2003Jun 27; 75 12 2029 2033
When good kidneys pump badly’: outcomes of deceased donor renal allografts with poor pulsatile perfusion characteristics. Transpl Int Guarrera J. V Goldstein M. J Samstein B Henry S Reverte C Arrington B et al 2010Apr 1; 23 4 444 446
Ernest van Heurn LW, Parkkinen J, Buurman WA. Redox-active iron released during machine perfusion predicts viability of ischemically injured deceased donor kidneys. Am J Transplant De Vries B Snoeijs M. G Von Bonsdorff L 2006Nov; 6 11 2686 2693
Ross H Escott M. L Gaseous oxygen perfusion of the renal vessels as an adjunct in kidney preservation. 1979Nov; 28 5 362 364
Fischer J. H Kulus D Hansen-schmidt I Isselhard W Adenine nucleotide levels of canine kidneys during hypothermic aerobic or anaerobic storage in Collins solution.Eur Surg Res 1981 13 2 178 188
Treckmann J. W Paul A Saad S Hoffmann J Waldmann K. H Broelsch C. E et al Primary organ function of warm ischaemically damaged porcine kidneys after retrograde oxygen persufflation.Nephrol Dial Transplant 2006Jul; 21 7 1803 1808
Treckmann J Nagelschmidt M Minor T Saner F Saad S Paul A Function and quality of kidneys after cold storage, machine perfusion, or retrograde oxygen persufflation: results from a porcine autotransplantation model 2009Aug; 59 1 19 23
Hyperbaric oxygen therapy. Part 1: history and principles. J Vet Emerg Crit Care (San Antonio) Edwards M. L 2010Jun; 20 3 284 288
Hyperbaric oxygen therapy. Part 2: application in disease. J Vet Emerg Crit Care (San Antonio) Edwards M. L 2010Jun; 20 3 289 297
Muralidharan V Christophi C Hyperbaric oxygen therapy and liver transplantationHPB (Oxford) 2007 9 3 174 182
Guibert E. E Petrenko A. Y Balaban C. L Somov A. Y Rodriguez J. V Fuller B. J Organ Preservation: Current Concepts and New Strategies for the Next DecadeTransfus Med Hemother 2011 38 2 125 142
Pegg D. E Wusteman M. C Foreman J Metabolism of normal and ischemically injured rabbit kidneys during perfusion for 48 hours at 10 C. 1981Nov; 32 5 437 443
Gaseous oxygen persufflation or oxygenated machine perfusion with Custodiol-N for long-term preservation of ischemic rat livers? Cryobiology Stegemann J Hirner A Rauen U Minor T 2009Feb; 58 1 45 51
Minor T Isselhard W Yamamoto Y Obara M Saad S The effects of allopurinol and SOD on lipid peroxidation and energy metabolism in the liver after ischemia in an aerobic/anaerobic persufflation.Surg Today 1993 23 8 728 732
Hosgood S. A Nicholson M. L The role of perfluorocarbon in organ preservationTransplantation 2010May 27; 89 10 1169 1175
Jr, Gollan F. Clark L. C Survival of mammals breathing organic liquids equilibrated with oxygen at atmospheric pressure.Science 1966Jun 24; 152 730 1755 1756
Brandhorst H Asif S Andersson K Theisinger B Andersson H. H Felldin M et al A new oxygen carrier for improved long-term storage of human pancreata before islet isolation 2010Jan 27; 89 2 155 160
Maluf D. G Mas V. R Yanek K Stone J. J Weis R Massey D et al Molecular markers in stored kidneys using perfluorocarbon-based preservation solution: preliminary resultsTransplant Proc 2006Jun; 38 5 1243 1246
Marada T Zacharovova K Saudek F Perfluorocarbon improves post-transplant survival and early kidney function following prolonged cold ischemiaEur Surg Res 2010 170 EOF 178 EOF
Hosgood S. A Mohamed I. H Nicholson M. L The two layer method does not improve the preservation of porcine kidneys.Med Sci Monit 2011Jan;17(1):BR 27 33
Berkowitz H. D Mendham J Miller L. D Importance of circulating microparticles for optimal renal perfusion.Surg Forum 1973 24 293 295
Berkowitz H. D Mccombs P Sheety S Miller L. D Sloviter H Fluorochemical perfusates for renal preservation.J Surg Res 1976Jun; 20 6 595 600
Honda K Fundamental and clinical studies on intracadaveric organ perfusion with Fluosol-DA.Prog Clin Biol Res 1983 122 327 330
Thuillier R Dutheil D Trieu M. T Mallet V Allain G Rousselot M et al Supplementation With a New Therapeutic Oxygen Carrier Reduces Chronic Fibrosis and Organ Dysfunction in Kidney Static Preservation.Am J Transplant 2011Sep; 11 9 1845 1860
Johnson J. L Dolezal M. C Kerschen A Matsunaga T. O Unger E. C In vitro comparison of dodecafluoropentane (DDFP), perfluorodecalin (PFD), and perfluoroctylbromide (PFOB) in the facilitation of oxygen exchange.Artif Cells Blood Substit Immobil Biotechnol 2009 37 4 156 162
Lundgren C. E Bergoe G. W Tyssebotn I. M Intravascular fluorocarbon-stabilized microbubbles protect against fatal anemia in rats.Artif Cells Blood Substit Immobil Biotechnol 2006 34 5 473 486
Jr, Leonard EF. Daniels F. H Mccabe R. E The use of hemoglobin solutions in kidney perfusions.Crit Rev Biomed Eng 1984 9 4 315 345
DelVecchio P, Amyot K, Haisch C, Clarke J. Brasile L Organ preservation without extreme hypothermia using an Oxygen supplemented perfusate.Artif Cells Blood Substit Immobil Biotechnol 1994 22 4 1463 1468
Humphreys M. R Ereth M. H Sebo T. J Slezak J. M Dong Y Blute M. L et al Can the kidney function as a lung? Systemic oxygenation and renal preservation during retrograde perfusion of the ischaemic kidney in rabbitsBJU Int 2006Sep; 98 3 674 679
Gage F Leeser D. B Porterfield N. K Graybill J. C Gillern S Hawksworth J. S et al Room temperature pulsatile perfusion of renal allografts with Lifor compared with hypothermic machine pump solutionTransplant Proc 2009Nov; 41 9 3571 3574
Regner K. R Nilakantan V Ryan R. P Mortensen J White S. M Shames B. D et al Protective effect of Lifor solution in experimental renal ischemia-reperfusion injuryJ Surg Res 2010Dec;164(2):e 291 7
Bonventre J. V Yang L Cellular pathophysiology of ischemic acute kidney injuryJ Clin Invest 2011Nov 1; 121 11 4210 4221
Bonventre J. V Pathophysiology of AKI: injury and normal and abnormal repair.Contrib Nephrol 2010 165 9 17
Hosgood S. A Bagul A Kaushik M Rimoldi J Gadepalli R. S Nicholson M. L Application of nitric oxide and carbon monoxide in a model of renal preservation.Br J Surg 2008Aug; 95 8 1060 1067
Oruc O Inci K Aki F. T Zeybek D Muftuoglu S. F Kilinc K et al Sildenafil attenuates renal ischemia reperfusion injury by decreasing leukocyte infiltrationActa Histochem 2010Jul; 112 4 337 344
Nafar M Sahraei Z Salamzadeh J Samavat S Vaziri N. D Oxidative stress in kidney transplantation: causes, consequences, and potential treatment.Iran J Kidney Dis 2011Nov; 5 6 357 372
Savas M Yeni E Ciftci H Yildiz F Gulum M Keser B. S et al The antioxidant role of oral administration of garlic oil on renal ischemia-reperfusion injury.Ren Fail 2010Jan; 32 3 362 367
Chatterjee P. K Novel pharmacological approaches to the treatment of renal ischemia-reperfusion injury: a comprehensive reviewNaunyn Schmiedebergs Arch Pharmacol 2007Oct;376( 1 EOF 43 EOF
Jr, Tolkoff-Rubin N, Preffer FI, et al. Haug C. E Colvin R. B Delmonico F. L Auchincloss H A phase I trial of immunosuppression with anti-ICAM-1 (CD54) mAb in renal allograft recipients. 1993Apr; 55 4 766 72discussion 772-3.
Harlan J. M Winn R. K Leukocyte-endothelial interactions: clinical trials of anti-adhesion therapy.Crit Care Med 2002May;30(5 Suppl):S 214 9
Edelstein C. L Ling H Schrier R. W The nature of renal cell injury.Kidney Int 1997May; 51 5 1341 1351
Yates P. J Hosgood S. A Nicholson M. L A biphasic response to nitric oxide donation in an ex vivo model of donation after cardiac death renal transplantation.J Surg Res 2012Jun 15; 175 2 316 321
Dal Secco DMoreira AP, Freitas A, Silva JS, Rossi MA, Ferreira SH, et al. Nitric oxide inhibits neutrophil migration by a mechanism dependent on ICAM-1: role of soluble guanylate cyclase 2006Aug; 15 1 77 86
Caumartin Y Stephen J Deng J. P Lian D Lan Z Liu W et al Carbon monoxide-releasing molecules protect against ischemia-reperfusion injury during kidney transplantation.Kidney Int 2011May; 79 10 1080 1089
Hanto D. W Maki T Yoon M. H Csizmadia E Chin B. Y Gallo D et al Intraoperative administration of inhaled carbon monoxide reduces delayed graft function in kidney allografts in Swine.Am J Transplant 2010Nov; 10 11 2421 2430
Hosgood S. A Nicholson M. L Hydrogen sulphide ameliorates ischaemia-reperfusion injury in an experimental model of non-heart-beating donor kidney transplantationBr J Surg 2010Feb; 97 2 202 209
Liu Y. H Lu M Bian J. S Hydrogen sulfide and renal ischemiaExpert Rev Clin Pharmacol 2011Jan; 4 1 49 61
Cassis P Azzollini N Solini S Mister M Aiello S Cugini D et al Both darbepoetin alfa and carbamylated erythropoietin prevent kidney graft dysfunction due to ischemia/reperfusion in rats 2011Aug 15; 92 3 271 279
Hu L Yang C Zhao T Xu M Tang Q Yang B et al Erythropoietin Ameliorates Renal Ischemia and Reperfusion Injury via Inhibiting Tubulointerstitial InflammationJ Surg Res 2011Jul 19.
Martinez F Kamar N Pallet N Lang P Durrbach A Lebranchu Y et al High dose epoetin beta in the first weeks following renal transplantation and delayed graft function: Results of the Neo-PDGF StudyAm J Transplant 2010Jul; 10 7 1695 1700
Aydin Z Mallat M. J Schaapherder A. F Van Zonneveld A. J Van Kooten C Rabelink T. J et al Randomized Trial of Short-Course High-Dose Erythropoietin in Donation After Cardiac Death Kidney Transplant RecipientsAm J Transplant 2012Mar 19.
The delayed administration of pHBSP, a novel non-erythropoietic analogue of erythropoietin, attenuates acute kidney injury. Mol Med Patel N. S Kerr-peterson H. L Brines M Collino M Rogazzo M Fantozzi R et al 2012Mar 8.
Eldaif S. M Deneve J. A Wang N. P Jiang R Mosunjac M Mutrie C. J et al Attenuation of renal ischemia-reperfusion injury by postconditioning involves adenosine receptor and protein kinase C activationTranspl Int 2010Feb; 23 2 217 226
Szwarc I Mourad G Argiles A Post-conditioning to reduce renal ischaemia/reperfusion injuryNephrol Dial Transplant 2009Jul; 24 7 2288 9author reply 2289-90.
Basu S Meisert I Eggensperger E Krieger E Krenn C. G Time course and attenuation of ischaemia-reperfusion induced oxidative injury by propofol in human renal transplantation.Redox Rep 2007 12 4 195 202
Snoeijs M. G Vaahtera L De Vries E. E Schurink G. W Haenen G. R Peutz-kootstra C. J et al Addition of a water-soluble propofol formulation to preservation solution in experimental kidney transplantation 2011Aug 15; 92 3 296 302
Zhuo W Liao L Xu T Wu W Yang S Tan J Mesenchymal stem cells ameliorate ischemia-reperfusion-induced renal dysfunction by improving the antioxidant/oxidant balance in the ischemic kidneyUrol Int 2011 86 2 191 196
Hara Y Stolk M Ringe J Dehne T Ladhoff J Kotsch K et al In vivo effect of bone marrow-derived mesenchymal stem cells in a rat kidney transplantation model with prolonged cold ischemia.Transpl Int 2011Nov; 24 11 1112 1123
Kwon O Miller S Li N Khan A Kadry Z Uemura T Bone marrow-derived endothelial progenitor cells and endothelial cells may contribute to endothelial repair in the kidney immediately after ischemia-reperfusionJ Histochem Cytochem 2010Aug; 58 8 687 694
Ciancio G Burke G. W Gaynor J. J Roth D Kupin W Rosen A et al A randomized trial of thymoglobulin vs. alemtuzumab (with lower dose maintenance immunosuppression) vs. daclizumab in renal transplantation at 24 months of follow-upClin Transplant 2008Mar-Apr; 22 2 200 210
Del Castillo D, Thymoglobulin Induction Study Group. Rabbit antithymocyte globulin versus basiliximab in renal transplantation. N Engl J Med Brennan D. C Daller J. A Lake K. D Cibrik D 2006Nov 9; 355 19 1967 1977