Kidney transplantation from non heart-beating donors

Clinical

Kidney transplantation from non heart-beating donors The use of non heart-beating donor (NHBD) kidneys to expand transplant programmes offers an answer to the problem of donor shortage. This source of kidneys is utilised by very few renal transplant units despite longstanding and growing evidence of equivalent graft function and survival, compared with cadaveric donor organs. This article reviews the selection criteria, technical approaches and logistical organisation involved in NHBD kidney retrieval and transplantation and outlines the evidence for graft function and survival, and patient outcome. The ethical and legal implications of running a NHBD programme are discussed, and some areas of current and likely future research are covered

Review N.R. Brook M.L. Nicholson The University Division of Transplant Surgery, Leicester General Hospital, Gwendolen Road, Leicester, LE1 6GF Correspondence to: N.R. Brook, The University Division of Transplant Surgery, Leicester General Hospital, Gwendolen Road, Leicester, LE1 6GF Email: nicho/[email protected]

Keywords: Non heart-beating donors, NHBD , kidney, transplantation Surg J R Coli Surg Edinb Irel., I December 2003,311-322

INTRODUCTION Renal tra nsplantation is the most cos teffec tive treatment for end- sta ge renal failure and improves quality of life, when compared with dialysis. The tran splant rate in the UK continues to be severely restricted by a lack of organ donors and the governm ent has set targets for increas ing tran splantation from the curre nt rate of approximate ly 1600 kidneys per annum to ove r 2500 by the year 20051 2006 (reco mmendations of the Quinq uennia l Review of UKT SSA 1998/99' ). The wider use of kidne ys from non heart-beat ing donors (NHBD) is one of the linchp ins of the government's strategy. In the year 200 J only 42 kidney transplants wer e performed from NHBD in the UK. The target set at the qu inquenn ial rev iew was to incre ase this fivefold to 2 10 NHBD transplants by 200512006. Despite renewed interest in NHBD kidney transplantation in the UK, very lew clinica l pro gramm es have been develop ed in the last 10 years and a numb er of unanswered questions remain about the use of NHBD kidneys. Thi s review summarises the current knowledge about NHBDs and addresses the question of how far NHBDs can go towards solving the orga n shortage probl em .

DEFINITION OF NHBDs The distinct ion between heart-b eating donors

(HBDs) and NHBDs lies in the mode of death . Heart-beating donors die because of an intrac ranial catas trophe resulting in death of the brain-stem (brain death ) whilst the patient is on a life support machin e. Non heart -beating donor organs are deri ved from patients who die as a result of a cardio-respiratory arrest (cardiac death). Fo llow ing cardiac arre st, the kidneys remain viable for about 40 minut es, and, if they can be coo led rapidl y during this period , they may be suitable for subsequent tran splantation. Th ere is noth ing new about the concept of NHB donation. Prior to the introduction, in the mid 1970s, of legislation defining the diagnosis of bra in-stem death, transplant organs were remov ed from NHBDs. The se donors were inten sive therapy unit (lTU) based, and had suffered head injuries or strokes that were deemed irrecov erable. Brain- stem death criteria could not be used to diagnose death at that time, and after a disc ussion with relatives a decision to withdraw treatment would follow; at that point the pot enti al for organ retri eval could be discussed with the next of kin. If permi ssion for organ donation was granted . the patient would be moved to the operatin g theatre where ventilatory support was withdraw n. Cessation of breathing was followe d by ca rdiac arrest, and only after this could organ retri eval begin . Th is plann ed withdrawa l of support meant that the interval

' The Reviewof the United Kingdom Transplant Service Authority (UKTSSA) 1998/99. Department of Health . 1999 http://wNw.doh.gov. uklorgandonation/execsum.pdf

© 2003Surg J R Coli Surg Edinb Irel 16; 311-322

The Royal Colleges ofSurgeons ofEdinburgh and Ireland

II

Perfusion fluid

TABLE 1. MAASTRICHT CATEGORIES OF NHBDS

-A

Category Vena cava

Aorta Intra -aortic double balloon cath eter

Venous vent

Figure 1: Diagram showing correct positioning ofthe double balloon kidney perfusion catheter

Definition Dead on arrival athospital

II

Unsuccessful resuscitation

III

Awaiting cardiac arrest

IV

Cardiac arrest in a brain-stem dead patient

in which the kidneys were at body temperature and not receiving oxygen (warm ischaemic interval) was minimised. This practice fell into disuse in the 1970s and 1980s in the UK because the introduction of brain-stem death criteria allowed organs to be retrieved in the heart-beating donor, the advantage being that the warm ischaemic period was eliminated.

CATEGORIES OF NHBDs

Four categories of NHBDs (Table 1) were identified at the first International Workshop on NHBDs in Maastricht.l-' These categories can be classified more simply into controlled and uncontrolled NHBDs depending on whether or not cardiac arrest was anticipated. Uncontrolled donors die without warning, and this leaves only a short period of time to prepare for the donation. In controlled donors, cardiac arrest is predicted in advance or planned by the withdrawal of life support and this gives more time to organise cooling of the kidneys within the body (in situ perfusion) and organ retrieval procedures. An example of a potential category 1 NHBD is a person who dies outside the hospital as a result of either a serious head injury or a high fracture of the cervical spine. These are unusual events and this is a rare source ofNHBDs. A further source of category 1 donors has been developed in Madrid where organs are procured from subjects who die suddenly on the street and are transported to hospital specifically for donation.' Category 2 donors are derived from patients who die after an unsuccessful attempt at cardiopulmonary resuscitation in hospital (either in the accident and emergency department or on a general ward). These are relatively common events and this provides the largest potential pool ofNHBDs. Category 3, and often category 4, provides controlled donors as they are derived from patients who are already receiving life support measures on an ITU. In category 3, the patients have usually suffered global and irrecoverable damage to the cerebral hemispheres without death of the brain-stem. After discussion with the family a decision may Figure 2:Acheck radiograph showing correct positioning ofthe double-balloon triple lumen catheter. The balloons are filled with dilute contrast be made to withdraw life support measures. Withdrawal of ventilator support and removal of the endotracheal tube leads to cessation of respiration followed by cardiac arrest.

It

The Royal Colleges ofSurgeons ofEdinburgh and Ireland

© 2003 Surg J R Coli Surg Edinb lrel1: 6;311-322

This procedure can be planned to take place either in, or close to, the operating theatres so that rapid organ retrieval is possible. Category 4 defines ITO based brain-stem dead donors who become unstable and suffer cardiac arrest before a heart-beating organ retrieval procedure can be performed. The instability of the patient gives some warning and this is a relatively controlled, albeit uncommon, type of NHBD. The important difference between controlled and uncontrolled NHBDs is the duration of warm ischaemic injury suffered by the kidneys prior to in situ cooling. In the controlled situation the warm time is limited to only 10-15 minutes, whereas in the uncontrolled situation warm times of 30-60 minutes are more usual. This is reflected in the fact that delayed graft function is almost inevitable following the transplantation of uncontrolled NHBD kidneys but is commonly less than 50% when controlled NHBD organs are used.

DONOR SELECTION The two most important criteria are donor age and the duration of the warm ischaemic interval. Most NHBD programmes use 60 years as the upper limit for donor age."? This is because kidney function declines with age, thus older kidneys tend to have more marginal function; this, in combination with warm ischaemia, can lead to poor graft function and ultimately poor graft survival rates. The amount of reversible warm ischaemia that the human kidney can sustain is not known. Most NHBD programmes exclude kidneys that have suffered prolonged warm times, the usual cut-off being in the region of 30-45 minutes. A comparison of the results of renal transplantation from controlled and uncontrolled NHB donors highlights the critical effect of the duration of warm ischaemia. In the controlled situation, where warm times are commonly in the region of 10-15 minutes, initial function rates of over 50% can be achieved." This is important as dialysis is avoided following transplantation. In contrast, transplants from uncontrolled NHBDs, where the warm time is usually more than 30 minutes, rarely demonstrate initial graft function. Post-transplant dialysis, therefore, is required for a period of some weeks during this time of delayed graft function whilst the kidney recovers from its initial insult.":" Donor age and warm time should be considered together; it may be possible, for example, to successfully transplant kidneys from a very young donor even if the warm time has extended to 60 minutes. The usual contra-indications to organ donation apply equally to NHBD and HBD. These are: malignant disease other than a number of carefully defined intra-cranial tumours, the presence of systemic infection, HIV and hepatitis B or C. Other adverse donor factors must be more stringently avoided than in HBDs. Most programmes avoid the use of NHBDs if there is a history of uncontrolled hypertension or of diabetes mellitus as these kidneys are likely to be damaged by the primary disease.

© 2003 Surg J R Coli Surg Edinb Irell. 6, 311-322

Figure 3: Machine for pulsatile kidney perfusion

Figure 4: Kidneys being preseNed inthe sterile cassette of a pulsation perfusion machine

The Royal Colleges ofSurgeons ofEdinburgh and Ireland

'I _

ORGANISATIONAL ASPECTS OF NHBDs All NHB donations take place as an emergency, and the principal requirement is a rapid response team trained in the techniques of in situ organ cooling and kidney retrieval. The team, which includes transplant co-ordinators and surgical staff, must be available 24 hours a day. The establishment of such a team is a major undertaking that requires considerable resources; this has undoubtedly been an important disincentive to the wider introduction of NHBD programmes in the UK and Ireland. Indeed, NHBD kidney transplantation has only been firmly established in the transplant units at Leicester, Newcastle and Guy's and St. George's Hospitals in London and Cambridge. These centres have developed programmes based on the Maastricht protocol , which includes the following principles: approval by the local medical ethics committee, diagnosis of death by doctors who are independent of the transplant team, the 10 minute rule (after declaration of cardiac death, the body is left untouched for a period of 10 minutes prior to placement on the external compression and ventilation device) , rapid in situ cooling using a catheter inserted into the aorta via the femoral artery, and organ retrieval using standard surgical techniques.

PRACTICAL CONSIDERATIONS There are differences in approach depending on whether the retrieval takes place in the accident department or on a general ward, and so these will be considered separately. Deaths in the accident and emergency (A&E) department usually take place in the resuscitation room where it is not appropriate to continue with organ cooling and retrieval. In the ideal situation, the A&E department will have a dedicated area, such as a small operating theatre or suture room, for organ perfusion techniques. This facility needs to be equipped with the sterile packs and surgical instruments for a femoral artery cut-down to allow insertion of perfusion catheters , and a refrigerator to store large volumes of perfusion fluid at 4°C. Once the 10 minute rule (see below) has been observed , cardiac massage and ventilation with 100% oxygen can be recommenced in an attempt to deliver some oxygenated blood to the kidneys. A mechanical resuscitation device, such as the Thumper" (Michigan Instruments, Grand Rapids, USA), is a useful piece of equipment in this situation as it releases medical and nursing staff from the task of external cardiac massage and ventilation. Efforts can then be turned to the process of in situ renal cooling, which is most commonly affected by placing a perfusion catheter into the aorta via a femoral artery cut-down in the groin . There are other techniques for renal cooling however (see next section). Uncontrolled NHB donations in the general hospital wards are less common and present more difficult logistical problems, as all the equipment for in situ renal cooling has to be taken to the ward . An alternative in this situation is to move the potential donor straight to an operating theatre as soon as death has occurred . This should not prolong the warm ischaemic time as most protocols include a 10 minute 'no touch' period

"

• • • • • The Royal Colleges ofSurgeons ofEdinburgh and Ireland

before the commencement of in situ cooling procedures. In the operating theatre the aortic perfusion catheter can be placed directly by performing an urgent laparotomy, rather than a femoral artery cut-down. This choice may depend on local hospital geography and facilities. Direct transfer and laparotomy are also suitable for ITU based controlled NHBDs.

KIDNEY COOLING TECHNIQUES Three main methods of in situ renal cooling have been described for NHBDs : intravascular cooling , intraperitoneal cooling and extracorporeal whole body cooling. The intravascular method is the simplest and is the one that has been adopted in the UK. This technique involves the use of a variant of the double balloon intra-aortic catheter originally described by Garcia-Rinaldi et al. (Figure I ).11 The cooling catheter is introduced via a femoral artery cut-down at the groin and needs to be positioned so that the lower balloon is inflated at the aortic bifurcation, and the upper balloon is above the origin of the renal arteries. The resultant isolation of the renal circulation allows the kidneys to be flushed with an appropriate preservation solution . An example is hyperosmolar citrate solution , cooled to 4°C. This washes blood out of the kidneys to prevent clotting, cools the organs so reducing metabolic requirements, and fills the renal substance with preservation fluid, so inhibiting cellular swelling. Although a femoral artery cut-down is a simple surgical procedure it does take a few minutes and is performed under some pressure as the warm ischaemic interval continues until the catheter is in place and in use. Difficulties are occasionally encountered as a result of narrow, tortuous or atheromatous iliac arteries. Incorrect positioning can also occur, the commonest error being to pull the lower balloon too far down into the iliac artery, which serves only to perfuse the opposite leg rather than the kidneys. This may be obvious by feeling the skin temperatures in the loin and the leg, but the best practice is to inflate the catheter balloons with dilute radiographic contrast media and then to check catheter positioning with an urgent plain abdominal x-ray (Figure 2).12 Several improvements to cooling catheter design have been made in recent years. Harder, less deformable plastics are now used to make insertion easier and the distance between the two balloons has also been increased to reduce the chance of incorrect positioning. The incorporation of secondary control balloons allows the operator to detect rupture of the main balloons. Experimental studies have shown that a flush pressure of 70mmHg leads to more effective cortical perfusion than lower pressures and some units therefore use a roller pump to accurately control the perfusate flow rate and a catheter that incorporates an extra lumen to allow continuous pressure monitoring,": " A return catheter, placed in the femoral vein at the groin, is used to vent the blood and perfusate being washed out of the kidneys. In order to reduce the resistance to flow at this point it is best to use a wide-bore catheter made from hard plastic © 2003 Surg J R Coli Surg Edinb Ire/t: 6; 311-322

(such as the catheters used for aortic arch cannulation during cardiopulmonary bypass) rather than a soft small gauge Foleytype catheter. Up to 20 litres of preservation fluid may be required and some units have chosen to use 5 litre containers for convenience and also to reduc e costs.':" The best perfusion solution for NHBD kidneys has not been established. Hyperosmolar citrate and histidine-tryptophanketoglutarate have been popular cho ices. The University of Wisconsin (UW) solution is perhaps the best solution for ischaemically damaged kidneys but is prohibitively expen sive (approximately £150 per litre) in such large volumes." A compromise can be achie ved by using UW solution as the final flush when the kidn eys have been retrieved from the donor.

OTHER METHODS OF COOLING KIDNEYS Groups in the USA and Spain have used alternative cooling techniques. In the intraperitoneal method, direct surface cooling of the kidneys is achieved by running cold Ringer's lactate solution into the per itoneal cavity via a chest drain , placed in the pelvis through a small infraumbilical incision." The fluid is drained out of the abdomen via a Fole y catheter placed through the same inci sion . Th is method has also been combined with intravascular cooling and there is some experimental evidence to suggest that thi s modificati on accelerates the rate of renal cooling. " It has also been show n that the intraperitoneal temperature can be reduced to l O''C in onl y a few minutes if an ice-alcohol immersed cooling coil is included in the intraperitoneal system.v" Extracorporeal whole bod y cooling can be performed using a simple cardiopulmonary bypa ss circuit. 19.20 Large bore catheters placed in the femoral arte ry and vein are connected to a roller pump, oxygenator and heat exch ang er. Th e system is primed with a saline/gelatine hydrosilate (Haemaccel") solution containing mannitol, bicarbonate and heparin. Normothermic bypass (37°C) is maintain ed for about 15 minutes after which a rapid cooling sequence is initiated by reducing the heat exchanger temperature to 4°C. The body core temperature (monitored by an oesophageal thermometer) is reduced to 15°C unt il the kidneys can be retr ieved at a forma l laparotomy. Thi s technique is rather complex, and requ ires relatively expensive equipment that need s some expertise to use. Its advantage is that it is possible to maintain hypothermic ex tracorporea l circul ation for many hours; this ma y be parti cularl y useful in cases where co nse nt for organ donation cannot be obtained immediatel y. Each of the different methods descr ibed has pro ved to be effective in the clinical setting but there is a pau cit y of work comparing the efficacy of the available techniques. Limitation of the warm ischaemic insult is an important principle in NHB donation and a priori it is suggested that more efficient cooling technique s might both impr ove the initial funct ion of NHBD kidneys and also improv e the yield of viable organs from NHBD . Th is is an important area for furth er research.

© 2003 Surg J R Coli Surg Edinb Irell: 6; 311-322

PRESERVATION METHODS The role of pulsatile machine perfusion Kidne y preservation by simple static cold storage (CS) III Ice has been adopted widely in the UK. This has been successful for HBD kidne ys as they suffer no warm ischaemic damage and relati vely limited cold ischaemic injury. Mach ine perfusion (MP), which has been used extensi vely in the USA, has found very little favour in the UK (Figure 3 and 4). It is more compl icated , more expensive and more labour intensi ve. MP, howe ver, may have advantages for NHBD kidneys as the y have suffered a greater ischaemic insult. At the mom ent there are few quality studi es for analysi s of this problem. Th ree comparisons of CS and MP for NHBD kidneys showed no overall difference in rates of delayed graft function. " :" A study from Japan randomised pairs of kidneys from the same donor to the two different storage techniques and found a higher incidence of initial graft function with MP.24 The wider application of this result is doubtful as the stud y was small (n= 13 per group) and only included controlled NHBDs . Perfusion technology has improved dramatically over the last two decades and further studies using modem machines and preservation solutions are warranted.

Legal and Ethical Issues Non heart-beating donation raise s a number of challenging legal and eth ical problems. These principally relate to the determination of death and to consent issues surrounding renal preservation procedures. It is vitally important that there is complete openness on these issues in the public domain as a loss of publ ic trust can have seriously deleterious effects on the organ donor rate from both NHBD and HBD alike .

The definition and diagnosis of death in NHBD In order to avoid a clear conflict of interest it is fundamental that doctors who are completely independent of the transplant team should determine the death of any potential donor. It is also helpful if hospitals have written resuscitation protoc ols in place that define the specific steps that must be completed in all cases of cardiac arre st befor e resuscitation can be pronounced unsuccessful and therefor e discontinued . This would usuall y consist of a 30 minut e per iod of cardia c massage that generates a femoral pulse and ventilation with 100% oxygen through an endotracheal tube, along with the use of appropriate intravenous or intracardiac drug s. If after this period the pup ils remain fixed and dilated , then it is usually clear that cardi ac arrest is irreversible . The difficul ty in the NHBD situation is that the diagnosis of death is made using card iac rather than brain criteria. The diagno sis of death by brain stem criteria is definiti ve and has been tightl y defined by law. In contrast, whilst the cessation of the heart beat is a simple concept of death that is easily under stood by members of the public, cardiac criteri a for death have not been clearly defined in law. The dead donor rule states that a donor must be dead before the retrie val of The Royal Colleges ofSurgeons ofEdinburgh and Ireland

t,

_

TABLE2. EARLY GRAFT FUNCTION Studyreference

Donor type

No. of transplants

PNF rate

DGF rate

8 (14) 9 (8)

34 (60) 40(35)

30 (53) 57 (50)

35 (67) 45(46)

18 (37) 29 (33)

Acute rejection

Wijnen etal.

NBHD HBD

57 114

Gonzalez Sergura etal.

NBHD HBD

52 98

Pacholczyket al.

NHBD HBD

76 100

3 (4) 3 (3)

50 (66) 33 (33)

50 (66) 46(46)

Cho etal.

NHBD HBD

229 8718

9 (4) 99 (1)

109 (48) 1912 (22)

43(1 9) 1209 (14)

Sanchez Fructuoso et al.

NHBD HBD

95 354

6 (6)

Metcalfe et al.

NHBD HBD

72 105

5 (7) 4 (4)

54 (80) 20 (19)

14 (24) 28 (31)

NHBD HBD

122 122

7 (6) 6 (5)

59 (48) 29 (24)

53 (49) 67 (55)

Weberet al.

41 (43) 152 (43)

Numbers in brackets are %; PNF: primary non function; DGF: delayed graft function organs and should not be killed by the act of organ retrieval itself." The essence of the problem is in defining a time period after which the absence of cardiac function is deemed to be "irreversible". The University of Pittsburgh protocol allows the dead donor rule to be applied after a period of only two minutes of asystole (defined as an absence of femoral pulse and electrical activity)." There has been vehement opposition to this definition on the grounds that cardiac auto-resuscitation remains a possibility after only two minutes ofcardiac standstill and that this interval does not necessarily lead to complete loss of neurological function." This casts a serious doubt on the definition of death in legal terms, as cardiac death criteria arc met at a point when brain stem criteria are not yet fulfilled . This point was considered at the first international workshop on NHBD in 1995. The consensus view was that the dead donor rule should only be applied after a period of 10 minutes during which there are no efforts to maintain circulation to the brain .' After this case the criteria for both cardiac and brain death will be met simultaneously.

Organ perfusion before family consent In the situation of an uncontrolled NHBD it is imperative to perform in situ organ cooling as soon as possible after death . The situation is straightforward if the next of kin

(see footnote *) is present at the time of death as consent for cannulation and in situ organ perfusion can be attained quickly. Once in situ perfusion (ISP) has been performed the family then have much more time to consider whether they wish organ retrieval to be performed. When the next of kin is not present at the time of death this raises the question of whether or not it is acceptable to perform cannulation and ISP without their permission. This question is one of the most controversial in NHB donation. The vast majority of sudden deaths in A&E departments come under the jurisdiction of the local coroner, who, therefore, must give permission ifISP is to be performed. At the moment in the UK only the Newcastle Coroners' Office permits ISP without written consent from the next of kin (see footnote **). The justification for performing organ perfusion without the consent of the next of kin is that this subsequently gives the family the opportunity to consider organ donation. This opportunity would be lost if too great a time interval elapses between death and organ cooling. The parallel situation for HBD is that artificial ventilation, intravenous fluids and inotropic drugs are used to support potential donors after brain stem death has been diagnosed to allow consent for organ retrieval to be obtained.' In situ perfusion is clearly a technique that enfranchises the next of kin and family . This

Footnotes: 'Ignoring occasional contentious problems astowho constitutes 'the next ofkin' andin what rank order their opinion should beheeded. Forexample, even long standing 'commonlawspouses' have nostatutory rights asnext ofkin, compared with estranged butnon·divorced spouse. "The role of the coroner in organ donation is under review by the Department of Health, see Human Bodies, Human Choices - The Law on Human Organs and TIssue in England and Wales; www.doh.govuk/tissue

II • The Royal Colleges ofSurgeons ofEdinburgh and Ireland •••

© 2003 Surg J R Call Surg Edinb lrell : 6; 311·322

should have widespread support as opinion polls show that 70% of the public are in favour of organ donation. In addit ion, the cannulation procedure performed for ISP is carried out through a short groin incision that does not disfigure the deceased. The law relating to NHBD varies across Europe. Spain has presumed consent ' opt-out' legislation in place and this allows for ISP without consent. In the Netherlands, legislation that makes a clear distinction between organ procurem ent, which require s written consent, and ISP, which may proceed without it, was passed in 1998. The current UK position, in which permission for ISP is left to the discretion of individual coroners, is difficult to ju stify. The government's recent consultation paper on tissues and organ transplantation has put this question before the public and it is to be hoped that this will lead to national legislation for in situ perfusion being introduced in the UK in the near future.

RESULTS OF NHBD KIDNEY TRANSPLANTATION Although it is widely acknowledged that there is a serious shortage of suitable organ donors , there has been a general reluctance to consider the use of NHBD kidneys in the UK. The fundamental question is: Are the results of NHBD kidney transplants good enough to support more extensive use of this particular donor source? To answer this question some care is needed when examin ing the literature, as there is considerable heterogeneity in the publi shed studies. Most series are from single centres and only contain relatively small numb ers of patients. Donor sources vary widely and the results of transplantat ion from controlled and uncontrolled donors tend to be reported togethe r rather than as sub-groups. There are also many differences in donor and recipient management protocols. The evidence base, therefore, is less than ideal. In the summary of result s that follow, the literature search was restricted to the time period 1990-2002 in order to review contemporary practice . This period corresponds to the period in which renewed interest in NHBD s has developed. Earlier reports provide less useful information as so many aspects of renal transplantation have changed enormously over the last decade. The results of small series (less than 50 NHBD kidney transplants) and studies that did not include a comparative series of transplants from heart-beating are not considered further. The results of seven selected publications containing a total of 703 NHBD kidneys are presented here (Tables 2 and 3). These seven series can be broadly divided into two types, four are case-control or matched paired studies in which kidneys from NHBD and HBD were matched for a numbe r of risk factors such as donor age, sex, transplant number, cold ischaemic times and HLA matching.6.JO.2R.29 The remaining three series compare the results of NHBD kidneys with an unmatched HBD 'c ontrol' series .9.30.31

Rates ofinitial graft function It is no surprise that NHBD kidneys have higher rates of primary non-function than comparative HBD kidneys © 2003 Surg J RColi Surg Edinb Irel1 : 6;311·322

(Table 2). At first sight the differences are not marked and do not reach statistical significance in most individual series. Nonetheless, when the results of the seven series included in Table 2 are pooled , the overall primary non-fun ction (PNF) rate is 5.8% (38/651 transplants) in NHBD kidneys compared with 1.3% (121/9 159 transplants) in HBD kidneys (X2 == 74.9 P
Delayed graft function rates Delayed graft function (DGF) in NHBD kidne ys is the clinical correlate of the development of acute tubular necrosis secondary to warm ischaemic injury. Non heart-beating donor kidney DGF rates vary considerably in the literature due to the heterogeneity of donor sources, but in all cases are higher than the respective rates for comparable HBD kidney transplant s (Table 2). Controlled NHBD kidneys with short warm times should achieve DGF rates that are comparable with HBD kidneys. An intriguing finding is that while most HBD kidney transplant series show a deleterious effect of DGF on graft survival rates, this does not appear to hold true for NHBD kidney transplants.P:" This apparent contradi ction may be due to the effects of bra in stem death, which has been shown experimentally to cause peripheral organ dysfunction as a consequence of massive upregulation of the genes for a number of pro-inflammatory cytokines." The sudden death of uncontrolled NHBD s should preclude the developm ent of such changes. The known consequences of DGF in NHBD kidneys are the requirement for post-operative dialysis support , longer inpatient stays and higher financial costs. It is certainl y wise to prepare patients receiv ing NHBD kidneys for the possibility of DGF and sometimes prolonged dialysis.

Acute rejection rates There is a reasonable amount of evidence to suggest that acute rejection rates are higher in kidneys with DGF, the theoretical explanation being an upregulation of MHC class II molecule s in ischaemic tissues." Despite this, there is little evidence to suggest that acute rejection occurs more frequentl y in NHBD kidneys (Table 2). The UNOS database-derived study, reported by Cho et aI. ( 1998), is the only comparative series to show a higher acute rejection rate in NHBD kidneys ( 19% versus l4% in HBD kidneys)." Although this differen ce reached statistically significant levels, the rejection rates for NHBD are still low and well within the margins of clinical acceptabil ity.

Chronic allograft nephropathy There is a paucity of evidence relating to the development of chronic allograft nephropathy in NHBD kidneys . The reported rates range widely from 8-25% but don't appear to exceed the rates associated with HBD. 25.J 8.40

The Royal Colleges ofSurgeons ofEdinburgh and Ireland _II:1II_ I' _

Graft survival rates All seven studies showed no statistically significant differences in allograft survival rates for NHBD and HBD (Table 3). The work from Zurich is the only one to include 10-year graft survival rates and these were 79% and 77% for kidneys from NHBD and HBD, respectively." The British Transplantation Society (BTS) published a standards document in 1998.4 1 This concludes that in order to be considered within current best practice, transplant centres utilising kidneys from HBD should achieve allograft survival rates of 80% and 60% after one and five years , respectively. These standards have been met in six out of seven of the series described here , the only series not meeting this criteria being the seminal work from Kootstra 's group in Maastricht. In this particular case, the results of the matched series of HBD kidney transplants also fell short of the BTS guidelines. A further analysis of the Leicester series compared graft survival rates of kidneys from HBD, NHBD and living donors." Despite again showing that NHBD kidneys have poorer initial graft function, there were no statistically significant differences in actuarial graft survival rates at 5 years post-transplant (per cent survival for living , HBD and NHBD = 78%, 75% and 79%, respecti vely) . The available evidence suggests that it is a misconception that NHBD kidneys have inferior graft survival rates . Further studies need to address the longer-term outcomes and to stratify results according to whether the NHBD donor source was controlled or uncontrolled.

Renal function A number of studies have reported that kidneys from NHBDs can achie ve post-transplant serum creatinine levels within the normal range .30 ,43-45 Three out of six of the comparative studies that recorded serum creatinines showed that NHBD kidneys lead to a decrement in renal function in comparison with HBD organs (Table 3), with mean serum creatinine levels 10-110 umol/l higher in the NHBD groups. In the Leicester experience, NHBD renal function falls into two distinct groups . Approximately half of recipients achie ve a normal serum creatinine level and the other half are left with a creatinine level of between 200-300 umol/l, at three months posttransplant. Rather surprisingly, the renal function in this latter group seems to remain stable for several years , suggesting that this may be a reflection of a sub-optimal, albeit stable, number of functioning glomeruli (unpublished Leicester data).

VIABILITY TESTING AND NHBD ORGAN QUALITY The high rate of primary non-function in NHBD kidney transplants has stimulated interest in the development of testing for the viability of the kidney pre-transplant. The ideal technique would be simple and quick to perform and would have high predictive value. The difficulty of achieving these goals should not be underestimated. A number of techniques that measure the degree of tissue injury are available, but these may not be that useful because they assess ischaemic injury per se, when what is really required is a test that measures the potential for recovery from injury ; the relationship between

TABLE 3. RENAL FUNCTION AND GRAFT SURVIVAL Study reference

Donor type

No. of transplants

Creatinine at 1 year

1-year graft survival

5-year graft survival

399 ±287 229 ± 226

73 73

54 55

52 98

205 145

92 98

68 77

NHBD HBD

76 100

155 142

82 90

67 73

Cho etal.

NHBD HBD

229 8718

Sanchez Fructuoso et al.

NHBD HBD

95 354

145 ± 11 136 ±4

85 88

84

NHBD HBD

72

105

177±11 158 ± 9

81 86

73 65

NHBD HBD

122 122

133 ± 53 142 ±62

86 87

74 76

Wijnen etal.

NHBD HBD

57 114

Gonzalez Sergura etal.

NHBD HBD

Pacholczyk et al.

Metcalfe et al.

Weber etal.

• • • • • The Royal Colleges ofSurgeons of Edinburgh and Ireland

83 86 83

© 2003 Surg J R Coli Surg Edinb Ire/I: 6; 311-322

Figure 5: TransplantsUNival rates forkidneys taken from live (LO), heart beating (HBD) and non heart-beating donors(NHBD)


]

c.

~

OJ c

70 60 50 40

~ 30

." 0

.J:J C

s

;z.

:%

,

20

•

x

aNHBD 0

ft

m Live . HBD

10 0 90 91 92 93 94 95 96 97 98 99

0

Year

Figure 6: Breakdown ofLeicester kidneys transplantnumbers by donor source 1992-2000. During thisperiod NHBD kidneysaccounted for 22%of thetotalprogramme

the level of injury and the potential for repair, which is not necessarily reciprocal.w'r " Current efforts in the development of viability tests are centring on renal pusatile machin e perfusion. This allow s the measurement of perfusate flow rates at a defined perfusion pressure and therefore the calcul ation of intra renal resistance. The assumption has been that kidneys that demon strate low per fusion flow rates and/o r high intra renal resis tance should be considere d unsuitable for transplantation and discarded. The results of the studies performed so far, at best, provide only indirec t evidence that these tests are useful indicator s of viability. Flow characteris tics certain ly do not seem to be useful in separating viable kidneys that will have DGF from those with initial function.v -" The main difficulty with using this test to predict viability is that the only way of being certai n kidneys with poor perfusion characteristics are indeed non-viab le would be to transpla nt them ; this may be difficult to justify. Th e measurement of lysosomal enzymes that are released from ischaemically dama ged tissues has also been advocated as a useful method of assessing renal viability." Machine perfusion provides a convenient method for the sequential ~

2003 Surg J R Coli Surg Edinb Irel!.' 6; 311·322

analysis of enzyme levels in the effluent perfusate. Recent interest has been directed towards the cytosolic enzyme glut athione-S-transferase (GST).49,55 This exist s in several different isoforms that have been shown to be site-spec ific, the 0. isoenzy me being confined to the proximal tube and the 1[ isoenzyme to the distal tubul e and collecting ducts of the kidney. Warm ischaemi a predominately damages proximal tubular cells and it has been shown that levels of o.-GST corre late with warm isch aemic time but level s of 1[-GST do not, 50 The problem with research performed so far is that whilst it is easy to demonstrate differen ces in the mean n -GST levels for groups of kidn eys that are viable and non- viable, there does not appear to be a threshold level of (l-GST that has sufficie nt sensitivity and spe cificity to define viability in an indivi dual kidney.P-" A novel approach to renal viability assessment is the use of normothermic pulsatile machine perfusion to re-establish renal function ex-vivo (Figure 3 and 4). An acellular perfluorocarbon based perfusate or mod ified autologous blood can provide sufficient oxygen to re-establish oxidative phosphorylation so that high energ y phosphate molecules, such as ATP, are regenerated more quickly than they are consumed.f -" Earl y experimental work with porcine, canine and bovine kidneys pump ed for six hours at 32°C have shown that these isolated perfusion techniques lead to the production of good volumes of urine, allow ing renal function to be assessed ex vivo. Further work needs to be done in this field , but there is the possibilit y that these methods will provide both a meth od of viability assessment and also the possibility of resuscitatin g ischaemica lly dam aged kidneys prior to transplantation by replen ishing stores of important metabolites such as ATP.

POTENTIAL FOR NHBDS TO SOLVE THE ORGAN SHORTAGE PROBLEM It is clear from a numb er of series that NHBD kidn eys can make a significant contribution to the overall transplant rate in individual centres. To take two examples, studie s in the Leicester (Figure 6) and Maastricht units over 10-year periods found that NHBD kidneys accounted for 22% and 40% of the total renal transplant programm es, respectivel y.i-" Nonetheless in both of these cases the overall transplant rate remained steady rather than being increased by NHB donation. Whilst it may be that without NHBD kidneys these programmes wo uld have suffered a 20--40% fall in the transplant rate , the concern is that the concentratio n of effort and resources on NHBD kidneys may have resulted in a decrease in the tran splant rate from other, possibly better quality, sources. In other wo rds, local NHBD transplantation may repre sent a redistribution of activity rather than new transplant activity. Changes in neuro-surgical practice in recent years may also have an effect on the proportion of HBD and NHBDs. It has become common practice recently to treat patients with severe head injuri es by raising a free-floating scalp flap. Th is is intended to prevent intracranial pressure rising to the point where the patient cones, resulting in death of the brai n stem. The Royal Colleges ofSurgeons ofEdinburgh and Ireland

Ii

_

In cases where the degree of primary brain injury proves to be irrecoverable, the consequence is that the patient will not meet the criteria for brain stem death but will suffer a cardiac death when life support is withdrawn. This change in neurosurgical practice may lead to an increase in the ratio ofNHBD to HBD donors from neurosurgical sources. The Maastricht group has tried to estimate the potential pool of NHBDs by performing a retrospective review of hospital deaths." This study identified 603 in-hospital deaths in a single year and estimated that these could have yielded between 27 and 56 NHBDs. This would have increased the local kidney transplant rate by a factor of between 2 and 4.5 fold. Terasaki et at. (1997) have suggested that the potential supply of NHBDs is even large enough to bridge the current gap between the supply and demand for renal transplantation in the USA. 53 This would need an extra 700 NHBDs per annum over a 14 year period to yield 10,000 more kidney transplants. If this model is correct, 60% of kidney transplants would be derived from NHBDs and the remaining 40% would come from HBD, thus totally eliminating the need to consider live donation. This model must be viewed cautiously, however, as the calculations are dependent on a number of optimistic assumptions that may not hold true. In addition, many transplant physicians and surgeons would not accept NHBD kidneys as an alternative to live donor kidney transplantation in view of the excellent results obtained from the latter source. Central funding provided through the United Kingdom Transplant Service, has been provided to establish new NHBD programmes in Sunderland (as a satellite of Newcastle), Leeds, St Mary's Hospital, Nottingham and Bristol. The vast majority of these new NHBD programmes will concentrate exclusively on controlled NHBDs. Whilst it is impossible to know at this stage how many purely controlled donors will be available, some of the current estimates seem optimistic. Controlled donors will be obtained almost exclusively from neurosurgical intensive care units. Whilst this source will undoubtedly provide a high yield of viable kidneys per donor, the overall potential number of controlled donors may be relatively limited. Controlled donors therefore provide low potential but a high yield of viable organs. This is in contrast to the uncontrolled situation in which the potential is vast but the yield of viable organs is lower as a result of more prolonged warm ischaemia. Non heart-beating donor kidneys have tended to be used locally rather than being shipped around the country as many units have registered with UK Transplant that they do not want to consider using them. Because of this NHBD kidney transplants tend to have shorter cold ischaemic times but poorer HLA matching. With the development of several new programmes there may be an increase in the sharing of NHBD kidneys.

of the new programmes that are currently being established in the UK to see if the good results achieved so far in a few dedicated centres can be reproduced more widely. There is still a paucity of long-term results and it will be important to define the incidence of chronic allograft nephropathy in these marginal donor kidneys. Other outcome measures such as quality of life and cost-effectiveness need to be addressed for NHBD kidneys and compared with the results from HBD and live donor sources. There is considerable scope for improving renal preservation solutions and storage techniques including pulsatile machine perfusion. The best immunosuppressive protocols are yet to be defined and there is an opportunity to study combination of the newer agents (interleukin-2 receptor monoclonal antibodies, mycophenolate mofetil and rapamycin) that may allow calcineurin inhibitor reduction or avoidance. Finally, efforts need to be concentrated on the development of accurate renal viability tests so that the incidence of PNF can be reduced.

Copyright: 4 November 2003

THE LINDSAY STEWART SPORTS FELLOWSHIP

([3 0

TH E ROYA L

, O OO )

COLLEGE of SURGEONS

Applications for funding

EDI N BURGH

(for one year) are invited

Founded 1505

from Members and Fellows

From here . heallh

of the College and Affiliates of the College who hold the Scottish Royal Colleges Diploma in Sports Medicine and are in good standing. Research must be undertaken in the UK. The clos ing date for receipt of applications is Friday 20 February 2004

SUGGESTIONS FOR FURTHER RESEARCH Non heart-beating donor kidneys transplantation raises many unanswered questions. It will be important to audit the results

i.

The Royal Colleges ofSurgeons ofEdinburgh and Ireland

© 2003 Surg J R Coli Surg Edinb Irell: 6;311·322

REFERENCES I.

22.

Proc 1995; 27: 2965. 2.

3.

perfusion pressure measurement. Transplant Proc 1993; 25:3169.

Kootstra G, Daeman JH, Oomen AP. Catagories of non-heart-beating

23.

preservation on early function of non-heart-beating donor kidneys.

Alvarez J, Iglesias J, Pulido O. et al. Type I non-heart-beating donors: Policy

Transplant Proc 1997; 29:3489.

24.

Transplantation 2000; 69:842-6.

6.

7.

graft function in cadaver donor renal transplantation. Transplantation 1984;

Matsuno N et al. Effectiveness of machine perfusion preservation as a

26.

viability determination method for kidneys procured from non-heart-beating

Medical Centre policy for the care of terminally ill patients who may become organ donors after death following the removal of life support; in

Metcalfe MS, Butterworth PC, White SA, et al. A case control comparison

Arnold RM, Youngner SJ, Schapiro R, Spicer CM (eds): Procuring Organs

of the results of renal transplantation from heart-beating and non-heart-

tor Transplant: The debate over non-heart-beating cadaver protocols. Baltimore, John Hopkins University Press, 1995, p55.

27.

28.

Wheatley TJ, Doughman TM, Veitch PS, et al.

Preservation of non-heart-beating donor kidneys: a clinical prospective

asytolic donors using an intra-aortic balloon catheter. Br J S 1996; 83:962.

randornised case-control study of machine perfusion versus cold storage.

Garcia-Rinaldi R, Lefrak EA, Defore Ww, et al. In situ preservation of

Transplantation ?roc 200 I; 33:847.

30.

Weber M, Dindo D, Demartines N ct al.

Pegg DE, Foreman J, Rolles K.

22] -5.

Kidney transplantation from 31.

Metabolism during preservation and

viability of ischaemically injured canine kidneys.

IllS. 32.

Light JA, Barhyte DY, Gage FA, Sasaki TM, Aquino AO

Long-term graft

Transplantation 1988; 45: 122.

33.

Howard RJ, Pfaff WW, Brunson ME, ct al. Increased incidence of rejection

34.

Sanchez-FructuosoAI, Prats D, Torrentc J, et a!' Renal transplantation from

Lloveras J, Puig JM, Cerda M, et al. Newly developed four lumen catheter for in situ renal perfusion of non-heart-beating donors that provides

in patients with delayed graft function

non-heart-beating donors: a promising alternative to enlarge the donor pool.

Booster MH et al. University of Wisconsin solution is superior to histidine

Journal American Society ofNephrology 2000; 11:350-8.

35.

Transplantation 1994; 58: 979-84.

Light JA, Kowalski AE, Ritchie WO, el al.

Transplantation 1992; 53:5.

36. New profile of cadaveric

Koyama I, Hoshino T, Nagashima N ct al.

A new approach to

Szostek M, Danielewicz

R, Lagiewska B et al. Successful transplantation

of kidneys harvested from cadaver donors at 71 to 259 minutes following

donors: What are the kidney donor limits') Transplant Prot: 1996; 28:17.

cardiac arrest. Transplant 37.

Proc 1995; 27:2901-2.

Gulanikar AC, MacDonald AS, Sungurtekin U et al. The incidence and

kidney procurement from non-heart-beating donors: Core cooling on

impact of early rejection episodes on graft outcome in recipients of first

cardiopulmonary bypass. Transplant Proc 1989; 21: 1203.

cadaver kidney transplants. Transplantation 1992; 53:323.

Gomez M, Alvarez J, Arias J, et al. Cardiopulmonary bypass and profound

38.

hypothermia as a means for obtaining kidney grafts from irreversible cardiac

University of Pittsburgh Medical Centre Policy and Procedure Manual. Kennedy Institute of Ethics Journal 1992: 3:AI-AI5

© 2003 Surg J R Coli Surg Edinb Irell: 6,311-322

Castelao AM. et al. Update of our experience in long-term renal function of kidneys transplanted from non-heart-beating cadaver donors. Transplant

arrest donors: Cooling technique. Transplant Proc 1993; 25: 150 I. 21.

Cecka JM, Cho YW, Terasaki PI: Analyses of the UNOS Scientific Renal Transplant Registry at three years - early events affecting transplant success.

Anaise D et al. Organ procurement from non-heart-beating cadaver donors. Transplant Proc 1989; 21: 1211-4.

20.

Clin Transplant 1994; 8:527.

perfusion pressure monitoring. Tramp/ant Proc 1995; 27:2909.

tryptophan ketoglutarate for preservation of ischemically damaged kidneys.

19.

Halloran P, April M, Farewell V, for the Ontario Renal Transplant Research Group: Factors influencing early function in cadaver kidney transplants.

survival after transplantation with kidneys from uncontrolled non heartbeating donors. Transplantation 1999;68: I910-11.

Rosenthal JT, Danovitvh GM, Wilkinson A et a!. The high cost of delayed graft function in cadaver renal transplantation. Transplantation 1991; 51:

Transplantation] 984;

38:78.

18.

Cho YW, Tcrasaki PI, Cecka JM, Gjertson DW. Transplantation of kidneys from donors whose hearts have stopped beating. N Engl J Med 1998; 338:

donors without a heartbeat. N Engl J MeJ 2002; 347:248-255.

17.

van der Vliet JA, Kievit JK, Hene RJ, Hilbrands LB, Kootstra G.

Kidney retrieval from

application. Ann Surg 1975; 182:576.

16.

Orloff MS, Reed AI, Erturk E, et a!' Non-heart-beating cadaveric organ donation. Ann Surg 1994; 220:578.

29.

cadaver kidneys for transplantation: Laboratory observations and clinical

15.

Fox RC. "An ignoble form of cannibalism". Reflections on the Pittsburgh

protocol for procuring organs from non-heart-beating cadavers. Kennedv

lnst. EthicsJ 1993; 3:231-9.

Gonzalez Segura C, Castelao AM, Torras J, et al. Long term follow up of

2948-50.

14

DeVita MA, Snyder JV: Development of the University of Pittsburgh

donors. Transplant Proc 1994; 26: 2421-2.

transplanted non-heart-beating donor kidneys. Transplant Proc 1995; 27:

13.

Sanfilippo F, Vaughn WY, Specs EK, et al. The detrimental effects ofdelayed

38:643.

Transplant International 1996; 9:415.

12.

situ

Light JA et al. A rapid organ recovery program for non-heart-beating

of delayed graft function and acute rejection on renal transplant survival.

II.

111

donors. Transplant Proc 1997; 29: 3553-6.

Nicholson ML, Wheatley TJ, Horsburgh T. er al. The relative influence

10.

Effect of combination

kidney procurement. Transplant Proc 1993; 25: 1516. 25

beating donors. Transplantation 200 I, 71: I 556-9.

9.

Matsuno N, Kozaki M, Sakurai E, et a!'

cooling and machine perfusion preservation on non-heart-beating donor

Balupuri S, Buckley P, Snowden C, et al. The trouble with kidneys derived from the non-heart-beating donor: a single centre 10-year experience.

5.

Daemen JH, de Vries B, Kootstra G: The effect of machine perfusion

donors. Transplant Proc 1995; 27: 2893-4.

and results (Abstract). Transplant Proc 1997 29:3552.

4.

Lloveras J, Puig JM, Cerda M, et a!' Optimisation of in situ perfusion of non-heart-beating donors: Four-lumen catheter developed for continuous

Kootstra G. Statement on non-heart-beating donor programs. Transplant

Proc 1993; 25: 1513-5. 39

Stubenitsky BM, Booster MH, Nederstigt AP et al. Kidney preservation in he next millennium. Transplant International] 999; 12:83.

The Royal Colleges ofSurgeons ofEdinburgh and Ireland

40.

4 1.

Cho YW, Terasaki PI, Cecka JM. I1igh kidney graft survival rates using

6.

ischaemically damaged kidneys into the machine perfusate - relevance to

British Transplantation Society: Towards Standards for Organ Tissue

viability assessment. Transplant Proc 1997; 29:3591. 51.

Nicholson ML, Metcalfe MS. White SA, et al. A comparison of the results

Guillard G, Rat P, Haas 0 , et al. Renal harvesting after in situ cooling

Hoshinaga K. Fujita T, Naide Y et al. Early prognosis of263 renal allografts

KozakiM, MatsunoN, Tamaki T et al. Procurement of kidney grafts from

SouthardJH, SenzigKA, Hoffman RM et al. Energymetabolism in kidneys stored by simple hypothermia. Transplant Proc 1977;9:1535.

Codd JE, Garvin PJ, Morgan R et al. Allograft viability determined by

57.

Brasile L, Clarke J, Green E, Haisch C. The feasibility of organ preservation at warmer temperatures. Transplant Proc. 1996; 28: 349-51.

enzyme analysis. Transplantation 1979;28:447 Daeman JW, Oomen AP, Janssen MA et aJ. Glutathione S-transferase as

58.

Proc 1996; 28:105.

non-heart-beating donor kidneys. Transplantation 1997; 63:89. Kievit JK, Oomen AP, Janssen MAet al. Viabilityassessment of non-heart-

Daemen IHC, de Wit RJ, Bronkhorst MWGA, et al. Non-heart-beating donor program contributes 40% of kidneys for transplantation. Transplant

predictor of functional outcome in transplantation of machine preserved

49.

KievitJK, OomenAP,de Vries B et al. Update on the resultsof non-heartbeatingdonor kidney transplants. TransplantProc 1997;29:2989.

56.

447-50.

48.

Daemen JHC, Heineman E, KOOIstra G. Viability assessmentof non-heart-

27:2906. 55.

AbendrothD, SchillingM. Fenzlein PG, Land W. Pretransplant assessment of renal viabilitydetermined by enzyme analysis. Transplantation 1979;28:

47.

Terasaki PI, Cho YW, Cecka JM. Strategy for eliminating the kidney

beatingdonor kidneys during machine preservation. Transplant Proc 1995;

non-heart-beating donors. Transplant Proceedings 1991;23:2575. 46.

Upregulation of major histocompatibility complex-

shortage. Clin Transplant J997:p265. 54.

Transplant Proceedings 1995; 27:703. 45.

Shackleton CR.

Proc 1998; 30:4264-6. 53.

harvested from non-heart-beating cadavers using in situ cooling technique.

Pacholczyk MJ, Lagiewska B, Szostek M, et al. Transplantation of kidneys

expression under ischaemic conditions in experimental models. Transplant

by intra aortic double balloon catheter. Transplant Proceedings 1993; 25:

44.

glutathione S-transferase (nGST) from

Transplant International 1996;9: Supplement I : S81-S83. 52.

1505.

11

harvested from non-heart-beatings donors: early and long-term results.

of renal transplantation from non-heart-beating. conventional cadaveric and living donors. Kidney International 2000; 58:2585-2591. 43.

Kievit JK, Nederstigt AP, Oomen APA, et al. Release of alpha glutathione S-transferase (alphaGST) and

Transplantation in the United Kingdom. 2003 Richmond BTS. 42.

50.

non-heart-beating trauma donors. Transplant Proceedings 1998; 30:3795-

59.

beating donor kidneys by alpha glutathione S-transferase in the machine

DaemenJHC, OomenAPA, Kelders WPA, et aJ. The potential pool of nonheart-beating kidney donors. Clin Transplant 1997; 11:149.

perfusate. Transplant Proc 1997; 9:1381.

ROYAL COLLEGE OF SURGEONS IN IRELAND SURGICAL TRAVELLING FELLOWSHIP 2004 Applications are invited for the RCSI Surgical Travelling Fellowship commencing l" July 2004. The object of the award is to promote the acquisition of additional surgical skills and knowledge that will contribute to the advancement of surgical science and practice in Ireland. The Fellowship is open to Irish graduates who are Fellows or Associate Fellows of the College and who are in surgical training at the time of application. The Fellowship , which must be full-time, is tenable for one year in Ireland or abroad and includes a stipend and travel allowance . Closing date:

Friday 2nd January 2004

Application forms and further particulars are available from: Ms G Conroy Office of the Director of Surgical Affairs 123, St. Stephen 's Green , Dublin 2. Tel: 4022187 Fax: 8102901. http://www.rcsi.ie Professor WA Tanner Director of Surgical Affairs

'1

The Royal Colleges ofSurgeons ofEdinburgh and Ireland

e-mail: gconroy @rcsi.ie

ReSI © 2003 Surg J R Coli Surg Edinb Ire/I: 6: 311·322