Clinical Review

Kidney transplantation from non heart-beating donors

N.R. Brook and 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: nicholasbrook@fastmail.fm

Introduction Definition of NHBDs Categories of NHBDs Donor selection Kidney cooling techniques

Other methods of cooling kidneys Preservation methods Results Potential for NHBDs References

Keywords: Non heart-beating donors, NHBD, kidney, transplantation
Surg J R Coll Surg Edinb Irel., 1 December 2003, 311-322

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

INTRODUCTION
Renal transplantation is the most costeffective treatment for end-stage renal failure and improves quality of life, when compared with dialysis. The transplant rate in the UK continues to be severely restricted by a lack of organ donors and the government has set targets for increasing transplantation from the current rate of approximately 1600 kidneys per annum to over 2500 by the year 2005/2006 (recommendations of the Quinquennial Review of UKTSSA 1998/99*). The wider use of kidneys from non heart-beating donors (NHBD) is one of the linchpins of the government’s strategy. In the year 2001 only 42 kidney transplants were performed from NHBD in the UK. The target set at the quinquennial review was to increase this fivefold to 210 NHBD transplants by 2005/2006.

Despite renewed interest in NHBD kidney transplantation in the UK, very few clinical programmes have been developed in the last 10 years and a number of unanswered questions remain about the use of NHBD kidneys. This review summarises the current knowledge about NHBDs and addresses the question of how far NHBDs can go towards solving the organ shortage problem.

DEFINITION OF NHBDs
The distinction between heart-beating donors (HBDs) and NHBDs lies in the mode of death. Heart-beating donors die because of an intracranial catastrophe resulting in death of the brain-stem (brain death) whilst the patient is on a life support machine. Non heart-beating donor organs are derived from patients who die as a result of a cardio-respiratory arrest (cardiac death). Following cardiac arrest, the kidneys remain viable for about 40 minutes, and, if they can be cooled rapidly during this period, they may be suitable for subsequent transplantation.

There is nothing new about the concept of NHB donation. Prior to the introduction, in the mid 1970s, of legislation defining the diagnosis of brain-stem death, transplant organs were removed from NHBDs. These donors were intensive therapy unit (ITU) based, and had suffered head injuries or strokes that were deemed irrecoverable. Brain-stem death criteria could not be used to diagnose death at that time, and after a discussion with relatives a decision to withdraw treatment would follow; at that point the potential for organ retrieval could be discussed with the next of kin. If permission for organ donation was granted, the patient would be moved to the operating theatre where ventilatory support was withdrawn. Cessation of breathing was followed by cardiac arrest, and only after this could organ retrieval begin. This planned withdrawal of support meant that the interval 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.

*The Review of the United Kingdom Transplant Service Authority (UKTSSA) 1998/99. Department of Health . 1999. http://www.doh.gov.uk/organdonation/execsum.pdf

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

Figure 2: A check radiograph showing correct positioning of the double-balloon triple lumen catheter. The balloons are filled with dilute contrast

CATEGORIES OF NHBDs
Four categories of NHBDs (Table 1) were identified at thefirst International Workshop on NHBDs in Maastricht.^1,2

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 of NHBDs. 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.3 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 of NHBDs.

Category 3, and often category 4, provides controlled donors as they are derived from patients who are alreadyreceiving 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 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.

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 ITU 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.^4-7 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.

Figure 3: Machine for pulsatile kidney perfusion

Figure 4: Kidneys being preserved in the sterile cassette of a pulsation perfusion machine

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.⁸ 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.^9,10 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.

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 40C.

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^TM (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 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 1).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 40C. 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.^13-15

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 (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 reduce costs.^1,4

The best perfusion solution for NHBD kidneys has not been established. Hyperosmolar citrate and histidine-tryptophanketoglutarate have been popular choices. The University of Wisconsin (UW) solution is perhaps the best solution for ischaemically damaged kidneys but is prohibitively expensive (approximately £150 per litre) in such large volumes.¹⁶ A compromise can be achieved by using UW solution as the final flush when the kidneys 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 peritoneal cavity via a chest drain, placed in the pelvis through a small infraumbilical incision.⁸ The fluid is drained out of the abdomen via a Foley catheter placed through the same incision. This method has also been combined with intravascular cooling and there is some experimental evidence to suggest that this modification accelerates the rate of renal cooling.¹⁷ It has also been shown that the intraperitoneal temperature can be reduced to 10°C in only a few minutes if an ice-alcohol immersed cooling coil is included in the intraperitoneal system.^5,18

Extracorporeal whole body cooling can be performed using a simple cardiopulmonary bypass circuit.^19,20 Large bore catheters placed in the femoral artery and vein are connected to a roller pump, oxygenator and heat exchanger. The system is primed with a saline/gelatine hydrosilate (Haemaccel^®) solution containing mannitol, bicarbonate and heparin. Normothermic bypass (370C) is maintained 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 until the kidneys can be retrieved at a formal laparotomy. This technique is rather complex, and requires relatively expensive equipment that needs some expertise to use. Its advantage is that it is possible to maintain hypothermic extracorporeal circulation for many hours; this may be particularly useful in cases where consent for organ donation cannot be obtained immediately.

Each of the different methods described has proved to be effective in the clinical setting but there is a paucity 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 techniques might both improve the initial function of NHBD kidneys and also improve the yield of viable organs from NHBD. This is an important area for further research.

PRESERVATION METHODS

The role of pulsatile machine perfusion
Kidney preservation by simple static cold storage (CS) in ice has been adopted widely in the UK. This has been successful for HBD kidneys as they suffer no warm ischaemic damage and relatively limited cold ischaemic injury. Machine perfusion (MP), which has been used extensively in the USA, has found very little favour in the UK (Figure 3 and 4). It is more complicated, more expensive and more labour intensive. MP, however, may have advantages for NHBD kidneys as they have suffered a greater ischaemic insult. At the moment there are few quality studies for analysis of this problem. Three comparisons of CS and MP for NHBD kidneys showed no overall difference in rates of delayed graft function.^21-23 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 study 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 modern machines and preservation solutions are warranted.

Legal and Ethical Issues
Non heart-beating donation raises a number of challenging legal and ethical 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 public 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 protocols in place that define the specific steps that must be completed in all cases of cardiac arrest before resuscitation can be pronounced unsuccessful and therefore discontinued. This would usually consist of a 30 minute period of cardiac massage that generates a femoral pulse and ventilation with 100% oxygen through an endotracheal tube, along with the use of appropriate intravenous or intracardiac drugs. If after this period the pupils remain fixed and dilated, then it is usually clear that cardiac arrest is irreversible.

The difficulty in the NHBD situation is that the diagnosis of death is made using cardiac rather than brain criteria. The diagnosis of death by brain stem criteria is definitive and has been tightly defined by law. In contrast, whilst the cessation of the heart beat is a simple concept of death that is easily understood by members of the public, cardiac criteria for death have not been clearly defined in law. The dead donor rule states that a donor must be dead before the retrieval of organs and should not be killed by the act of organ retrieval itself.²⁵ 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).²⁶ There has been vehement opposition to this definition on the grounds that cardiac auto-resuscitation remains a possibility after only two minutes of cardiac standstill and that this interval does not necessarily lead to complete loss of neurological function.²⁷ This casts a serious doubt on the definition of death in legal terms, as cardiac death criteria are 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.¹ 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 if ISP 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.³ In situ perfusion is clearly a technique that enfranchises the next of kin and family. This  should have widespread support as opinion polls show that 70% of the public are in favour of organ donation. In addition, the cannulation procedure performed for ISP is carried out through a short groin incision that does not disfigure the deceased.

Footnotes: *Ignoring occasional contentious problems as to who constitutes ‘the next of kin’ and in what rank order their opinion should be heeded. For example, even long standing ‘common law spouses’ have no statutory rights as next of kin, compared with estranged but non-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.gov.uk/tissue

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 procurement, which requires 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 justify. 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 examining the literature, as there is considerable heterogeneity in the published studies. Most series are from single centres and only contain relatively small numbers of patients. Donor sources vary widely and the results of transplantation from controlled and uncontrolled donors tend to be reported together 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 results 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 NHBDs 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 number of risk factors such as donor age, sex, transplant number, cold ischaemic times and HLA matching.^6,10,28,29 The remaining three series compare the results of NHBD kidneys with an unmatched HBD ‘control’ series.^9,30,31

Rates of initial graft function
It is no surprise that NHBD kidneys have higher rates of primary non-function than comparative HBD kidneys (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-function (PNF) rate is 5.8% (38/651 transplants) in NHBD kidneys compared with 1.3% (121/9159 transplants) in HBD kidneys (.2 = 74.9 P<0.0001; relative risk = 0.8126, 95% CI 0.7447 - 0.8867). Primary non-function in HBD kidney transplants usually results from renal arterial or venous thrombosis. The excess rate of PNF in NHBD kidneys is likely to be due to ischaemic cortical necrosis after transplantation of a non-viable kidney.

Delayed graft function rates
Delayed graft function (DGF) in NHBD kidneys 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 transplants (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.^32-35 This apparent contradiction may be due to the effects of brain 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.³⁶ The sudden death of uncontrolled NHBDs should preclude the development 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 certainly wise to prepare patients receiving 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 molecules in ischaemic tissues.³⁷ Despite this, there is little evidence to suggest that acute rejection occurs more frequently in NHBD kidneys (Table 2). The UNOS database-derived study, reported by Cho et al. (1998), is the only comparative series to show a higher acute rejection rate in NHBD kidneys (19% versus 14% in HBD kidneys).³⁰ Although this difference reached statistically significant levels, the rejection rates for NHBD are still low and well within the margins of clinical acceptability.

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.^25,38-40

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.¹²

The British Transplantation Society (BTS) published a standards document in 1998.⁴¹ 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.⁸ 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%, respectively).

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 achieve 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 µmol/l higher in the NHBD groups. In the Leicester experience, NHBD renal function falls into two distinct groups. Approximately half of recipients achieve a normal serum creatinine level and the other half are left with a creatinine level of between 200-300 µmol/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 the level of injury and the potential for repair, which is not necessarily reciprocal.^26,46-53

Current efforts in the development of viability tests are centring on renal pusatile machine perfusion. This allows the measurement of perfusate flow rates at a defined perfusion pressure and therefore the calculation of intra renal resistance. The assumption has been that kidneys that demonstrate low perfusion flow rates and/or high intra renal resistance should be considered unsuitable for transplantation and discarded. The results of the studies performed so far, at best, provide only indirect evidence that these tests are useful indicators of viability. Flow characteristics certainly do not seem to be useful in separating viable kidneys that will have DGF from those with initial function.^53,54 The main difficulty with using this test to predict viability is that the only way of being certain kidneys with poor perfusion characteristics are indeed non-viable would be to transplant them; this may be difficult to justify.

The measurement of lysosomal enzymes that are released from ischaemically damaged tissues has also been advocated as a useful method of assessing renal viability.⁴⁶ Machine perfusion provides a convenient method for the sequential analysis of enzyme levels in the effluent perfusate. Recent interest has been directed towards the cytosolic enzyme glutathione-S-transferase (GST).^49,55 This exists in several different isoforms that have been shown to be site-specific, the a isoenzyme being confined to the proximal tube and the p isoenzyme to the distal tubule and collecting ducts of the kidney. Warm ischaemia predominately damages proximal tubular cells and it has been shown that levels of a-GST correlate with warm ischaemic time but levels of p-GST do not.⁵⁰ The problem with research performed so far is that whilst it is easy to demonstrate differences in the mean a -GST levels for groups of kidneys that are viable and non-viable, there does not appear to be a threshold level of a-GST that has sufficient sensitivity and specificity to define viability in an individual kidney.^48,49

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 modified autologous blood can provide sufficient oxygen to re-establish oxidative phosphorylation so that high energy phosphate molecules, such as ATP, are regenerated more quickly than they are consumed.^56,57 Early experimental work with porcine, canine and bovine kidneys pumped for six hours at 320C have shown that these isolated perfusion techniques lead to the production of good volumes of urine, allowing renal function to be assessed ex vivo.

Further work needs to be done in this field, but there is the possibility that these methods will provide both a method of viability assessment and also the possibility of resuscitating ischaemically damaged kidneys prior to transplantation by replenishing stores of important metabolites such as ATP.

POTENTIAL FOR NHBDs TO SOLVE THE ORGAN SHORTAGE PROBLEM
It is clear from a number of series that NHBD kidneys can make a significant contribution to the overall transplant rate in individual centres. To take two examples, studies 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 programmes, respectively.^7,58 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 would have suffered a 20-40% fall in the transplant rate, the concern is that the concentration of effort and resources on NHBD kidneys may have resulted in a decrease in the transplant rate from other, possibly better quality, sources. In other words, local NHBD transplantation may represent 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 injuries by raising a free-floating scalp flap. This is intended to prevent intracranial pressure rising to the point where the patient cones, resulting in death of the brain stem.

Figure 5: Transplant survival rates for kidneys taken from live (LD), heart beating (HBD) and non heart-beating donors (NHBD) 

Figure 6: Breakdown of Leicester kidneys transplant numbers by donor source 1992-2000. During this period NHBD kidneys accounted for 22% of the total programme

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 of NHBD 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.⁵⁹ 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 al. (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.

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

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Copyright: 4 November 2003

THE LINDSAY STEWART SPORTS FELLOWSHIP (£30,000)

THE ROYAL COLLEGE of SURGEONS of EDINBURGH

Applications for funding (for one year) are invited  from Members and Fellows 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 closing date for receipt of applications is Friday 20 February 2004

ROYAL COLLEGE OF SURGEONS IN IRELAND 
SURGICAL TRAVELLING FELLOWSHIP 2 0 0 4

Applications are invited for the RCSI Surgical Travelling Fellowship commencing 1st 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. e-mail: gconroy@rcsi.ie
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Professor WA Tanner
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