Kidney transplantation

Kidney transplantation

Transplantation Kidney transplantation Learning objectives Swati Karmarkar After reading this article, you should be able to: • name the four cat...

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Transplantation

Kidney transplantation

Learning objectives

Swati Karmarkar

After reading this article, you should be able to: • name the four categories of living donors and the five categories of deceased donors • explain the preoperative management of hyperkalaemia • list three strategies to optimize graft function intraoperatively during kidney transplantation.

Cathy Armstrong

Abstract replacement therapy (RRT) is needed to maintain life. Over recent years, improvements in surgical technique, immunosuppression and medical management of patients undergoing kidney transplantation have led this to be recognized as the best method of RRT. Guidelines from the UK Renal Association state that transplantation should be the RRT of choice for patients with established renal failure who are considered fit for major surgery and chronic immunosuppression. Approximately 2000 kidney transplants are performed every year in the UK. In 2007, the number of UK patients waiting for a kidney transplant was over 6400. This has increased by more than 40% in the last 10 years. Traditionally, most transplanted kidneys have come from deceased heart-beating donors, typically ventilated critical care patients diagnosed as brainstem dead, whose circulation is maintained until the organs are harvested. The increasing demand for organs has prompted consideration of ways to expand the pool of potential donors. In 2006, approximately 20% of kidney transplants from deceased donors had organs harvested from non-heart-beating donors. These are in effect marginal grafts. The numbers are limited by strict donor criteria (Table 1) and the need for prompt organ retrieval which is dependent on an organ retrieval team and theatre availability. Another valuable and increasing source is living-donor kidneys, which is in effect the gold standard in kidney transplantation. This is increasing significantly in the UK.

Approximately 2000 kidney transplants are performed every year in the UK. Owing to advances in surgical technique and immunosuppression therapy, transplantation is now the preferred method of renal replace-­ ment therapy for most patients with established renal failure (ERF). Donor organs have traditionally been harvested from deceased heart-­beating donors but other forms of donation (e.g. non-heart-beating donors and living donors) are increasingly being utilized. Patients with ERF have complex multisystem disease and are a high-risk group for anaesthesia and surgery. Cardiovascular disease is common and is the main cause of mortality following transplantation. Major preoperative considera-­ tions include evaluation of cardiorespiratory function and ­assessment of fluid and electrolyte balance. The main perioperative aim is to optimize graft function. Strategies include careful fluid management aided by central venous monitoring, maintenance of a mean arterial pressure of 70–80 mm Hg and administration of corticosteroid and mannitol around the time of graft reperfusion. Postoperative care is on a specialist ward and managed by protocols addressing fluid, pain and immunosuppres-­ sion management. Living-donor kidney transplants now account for ­approximately one-third of all kidney transplants. Following a thorough evaluation process the living donor undergoes a unilateral nephrectomy performed either laparoscopically or as an open procedure.

Keywords donor; graft; immunosuppression; kidney; living donors; nephrectomy; renal transplant

Introduction

Aetiology and pathophysiology of established renal failure

In the UK, at the end of 2006 there were over 40,000 adults diagnosed with established renal failure (ERF). ERF is defined as chronic kidney disease with a glomerular filtration rate (GFR) <15 ml/min/1.73 m2 or which has progressed so far that renal

The commonest cause of ERF is diabetes mellitus, which accounts for approximately one-fifth of cases. Other causes include glom­ erulonephritis, pyelonephritis, renovascular disease, polycystic kidney disease and hypertension. The pathophysiological consequences of ERF are not limited to the kidney but affect many systems throughout the body (Table 2). Cardiovascular disease is up to 20 times more common in patients with uraemia than in the general population. In addition, long-term dialysis is itself associated with increased morbidity and mortality. Patients with ERF are, therefore, a particularly high-risk group to undergo anaesthesia and major surgery.

Swati Karmarkar MD(Anaesthesia) DA FRCA is Consultant Anaesthetist at Manchester Royal Infirmary, Manchester, UK. She qualified from Tver State Medical Institute, Russia, and trained in anaesthesia in Mumbai, India, West Yorkshire and North West Schools of Anaesthesia, UK. Her Specialist interests are anaesthesia for renal and pancreas transplants and regional anaesthesia for upper limb orthopaedics. Conflicts of interest: none declared.

Selection and evaluation for kidney transplantation In the UK most patients with ERF are considered for transplantation unless there are significant contraindications (Table 3). There is, however, significant variability in the listing criteria between the different UK renal units.

Cathy Armstrong FRCA is a Specialist Registrar in the North West School of Anaesthesia, UK. She qualified from Manchester University and is currently working at the Manchester Royal Infirmary. Conflicts of interest: none declared.

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Transplantation

exercising muscles is not adequate. An AT <11 ml/min/kg combined with inducible ischaemia would place the patient at highest risk for postoperative adverse cardiovascular events. A few studies have shown that optimizing nutrition, especially serum ­phosphorus, may improve CPET results for patients with ERF.

Non-heart-beating kidney donor categorization and selection criteria Categorization • Category 1: dead on arrival at hospital Must be witnessed sudden death with documented time of collapse and pre-admission resuscitation • Category 2: unsuccessful resuscitation Time and efficiency of resuscitation must be documented (usually A&E patients) • Category 3: awaiting cardiac arrest Patients in whom death is inevitable but who do not fulfil the brainstem dead criteria • Category 4: cardiac arrest in brainstem dead cadaver Patients diagnosed brainstem dead who suffer an unexpected cardiac arrest (often awaiting arrival of organ retrieval team) • Category 5: unexpected cardiac arrest in a critical care unit

The matching process Donor and recipient matching, whether living or cadaveric kidney donation, is divided into three distinct areas: blood group and type matching, tissue type matching and the final crossmatch. Six antigens (major histocompatibility complexes), at three loci (A, B and DR), are considered during tissue matching. Although the best outcomes may still be achieved with a six-antigen match, major developments in immunosuppression have ensured that even fully mismatched organs could have a favourable outcome. This is especially so in living donor transplantation. A lympho­cytotoxicity cross-match between donor lymphocytes and recipient serum is the final test performed. If the cross-match is positive then the risk of hyperacute rejection necessitates consideration of the next potential recipient.

 Donor selection criteria • Age <65 years • Warm ischaemia time <40 minutes • Time from hypotension <55 mmHg systolic to cold perfusion of the organs (cooling solution infused via balloon pump) • No history of renal impairment • No uncontrolled hypertension or complicated insulindependent diabetes • No uncontrolled systemic sepsis or malignancy

Preoperative assessment The cold ischaemic time of the donor kidney should ideally be less than 24 hours. It starts when the organ is cooled with a cooling solution during harvesting and ends when the kidney reaches physiological temperature during implantation. The longer the cold ischaemia time the greater the chance of delayed graft function (need for dialysis in the first week after kidney transplantation). Consequently, there is often limited time available for preoperative assessment on the day of surgery. The anaesthetic assessment in the immediate preoperative period should concentrate on reassessing co-morbidities and considering factors that can fluctuate in established renal failure especially fluid and electrolyte balance and haematological status (Table 2). Important considerations are signs of systemic volume overload, hyperkalaemia (>5.5 mmol/l) and acidosis. Any of these would necessitate dialysis or pharmacological correction before the procedure.

Table 1

In some patients even if one or more contraindications are present the risks of continuing long-term dialysis may outweigh those of undergoing transplantation (e.g. patients with severe vascular access problems). In these circumstances the decision to be listed for transplant must be between the patient and the clinicians with due consideration of the risks involved. The potential transplant recipient undergoes an extensive evaluation process before being activated on the transplant list. Patients with a suggestive family history or those over 50 are screened for the presence of pre-existing cancer. All patients are tested for the presence of viral diseases such as hepatitis B and C and human immunodeficiency virus (HIV). The main emphasis is placed on evaluation and optimization of the cardiovascular system as cardiovascular disease is the main cause of mortality following transplantation. Echocardiography is important to screen for structural cardiac abnormalities and, since conventional ECG exercise testing can be difficult to interpret, dobutamine stress echocardiography or thallium dipyridamole stress tests are often considered, especially in patients with diabetes. If reversible ischaemia is demonstrated, then coronary angioplasty, stenting and revascularization should be considered. In patients with significant cardiovascular co-morbidity cardiopulmonary exercise testing (CPET) is performed. CPET simultaneously evaluates ventricular function, respiratory function and myocardial ischaemia. CPET grades operative risk based on anaerobic threshold (AT) and onset of myocardial ischaemia. The AT (ml/min/kg) is the point at which anaerobic metabolism is necessary to supplement the existing aerobic metabolism, that is, oxygen supply to the

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Surgical procedure A curvilinear incision is made from above the symphysis pubis to the anterior superior iliac spine. The donor kidney is placed in the iliac fossa, below the native kidney, which is typically left in situ. The iliac vessels are exposed extraperitoneally and anastomoses are made between the renal vein and the external iliac vein and the renal artery and the common, external or internal iliac artery. This will mean a period of vascular cross-clamping of the iliac artery and vein on the side of the implant. The ureter of the transplanted kidney is anastomosed to the bladder (Figure 1). A critical point in the operation is when the vascular clamps are removed and the transplanted kidney is reperfused.

Anaesthetic perioperative management General anaesthesia is considered the technique of choice. However, as this is an extraperitoneal procedure a combined spinal epidural technique without sedation has been used successfully 241

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Pathophysiological consequences of established renal failure Pathophysiological consequences of ERF Renal Uraemia Anuria Fluid overload

Cardiovascular and respiratory Ischaemic heart disease Hypertension Congestive cardiac failure Dysrhythmias Cardiomyopathy Uraemic pericarditis/effusion Hyperlipidaemia Pulmonary fibrosis Pleural effusions Haematological Anaemia Platelet dysfunction/coagulopathy Multiple previous blood transfusions: antibodies/acquired infections Immunosuppression Gastrointestinal Gastro-oesophageal reflux/peptic ulcer disease Delayed gastric emptying Nausea and vomiting Endocrine system Diabetes mellitus Secondary hyperparathyroidism Electrolyte disturbances Hyperkalaemia Hypocalcaemia Central nervous system Autonomic/peripheral neuropathy Uraemic encephalopathy/convulsions Low mood, anxiety and depression Musculoskeletal system Myopathy/renal osteodystrophy

Anaesthetic preoperative considerations

Cause/course of ERF Renal replacement therapy regimen Current weight: ideally within 2 kg of dry weight Daily urine output AV fistula site Pre-existing cardiovascular or respiratory disease Evidence of congestive cardiac failure Review investigations from evaluation period Omit ACE inhibitors or angiotensin II antagonists on day of surgery Assess potential peripheral/central i.v. access sites

Recent use of anticoagulants, deranged thromboelastography Check full blood count and clotting profile Ensure 2 units of cross-matched blood available Blood products

Starvation period Consider use of proton pump inhibitor

Insulin sliding scale if required Check calcium Check urea and electrolytes If potassium >5.5 mmol/l consider further dialysis or medical management Consider anxiolytic premedication

History of neck involvement

ACE, angiotensin-converting enzyme; AV, arteriovenous; ERF, established renal failure; i.v., intravenous.

Table 2

is ­adequate in most cases. Care is taken not to place the NIBP cuff on the same side as an arteriovenous (AV) fistula. Invasive blood pressure monitoring is restricted for use in patients with marked cardiovascular compromise in order to protect potential fistula sites. A central venous catheter is inserted for intra­ operative central venous pressure monitoring and postoperative venous access. This is usually kept in place for 3 days for postoperative fluid management. Routine use of ultrasound guidance is ­ advocated as distorted anatomy from previous central lines and hypovolaemia following dialysis can make the ­ traditional

in patients considered to be high risk for general anaesthesia, usually because of poor respiratory function. The concerns with routine use of regional anaesthesia are an increased risk of epi­ dural haematoma (uraemic thrombasthenia and thrombocyto­ pathy, residual dialysis anticoagulation) and infection (long-term immunosuppression). Monitoring A five-lead ECG is used to allow accurate ST and dysrhythmia analysis. Non-invasive blood pressure (NIBP) monitoring

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Contraindications for kidney transplantation

Kidney transplantation a

• Predicted patient survival of less than 5 years, e.g. uncontrollable cancer, cardiovascular disease with a predicted risk of death greater than 50% at 5 years • Predicted risk of graft loss greater than 50% at 1 year, e.g. anti-glomerular basement membrane disease with circulating antibody • Patients unable to comply with immunosuppressant therapy, e.g. a history of non-compliance, especially previous failed transplant due to non-compliance • Immunosuppression predicted to cause life-threatening complications, e.g. unresolved chronic bacterial infection

Incision

Table 3

l­andmark technique difficult. The right internal jugular vein is preferred as the risk of stenosis is least at this insertion site. The femoral veins are avoided as the transplanted kidney is anastomosed to the external iliac veins. Other forms of cardiac output monitoring, such as oesophageal Doppler monitoring, is used to optimize fluid management. Temperature monitoring is mandatory in order to maintain normothermia to optimize graft function. Neuromuscular junction monitoring is essential owing to decreased clearance and potential for drug accumulation and residual neuromuscular blockade.

b

Diseased kidneys

Positioning The patient is placed supine on a warming mattress. Other warming devices such as a fluid warmer and forced air warming blanket are also used. AV fistula sites are protected. Graduated compression stockings and pneumatic compression devices for thromboembolism prophylaxis are applied.

Transplanted kidney Transplanted ureter

Bladder

c Aorta Vena cava

Induction and maintenance of anaesthesia Gaining peripheral intravenous (i.v.) access for induction can be difficult. Intravenous cannulae are not inserted in the same arm as a working AV fistula. Use of existing dialysis lines is avoided. Both i.v. induction with volatile-based maintenance and total intravenous anaesthetic (TIVA) techniques have been used.

Transplanted kidney Sutures

Rapid sequence induction and hyperkalaemia Suxamethonium can be safely used if the serum potassium (K+) is less than 5.5 mmol/l. If above this level, surgery may have to be delayed while the potassium level is treated by dialysis. Medical management using an insulin–dextrose infusion is instituted only if K+ is more than 6.5 mmol/l or if there are hyperkalaemia-related ECG changes. Eight units of human soluble insulin in 50 ml of 50% glucose is infused over 20 minutes. A fall in K+ should occur in 15 minutes with peak effects in 1 hour. The expected reduction in K+ per infusion is 0.65–1 mmol/l per infusion. Strict glucose monitoring is instituted every 30 minutes for 2 hours and 4 hourly thereafter. Calcium (10 ml of 10% calcium gluconate), a physiological antagonist of potassium, is given to prevent cardiac dysrhythmias. Alternatively, a modified rapid sequence induction with rocuronium may be used in case of emergency surgery after having instituted medical management of hyperkalaemia.

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Aorta Vena cava Ureter

Transplanted ureter Bladder

Figure 1

Isoflurane and desflurane are not nephrotoxic and are considered the volatile agents of choice. Exposure to <4 minimum alveolar concentration (MAC) hours of sevoflurane is not associated with renal toxicity.1 Studies of fluoride pharmacokinetics in patients with chronic kidney disease have proved sevo­ flurane to be a safe alternative. TIVA is a suitable option as the 243

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Transplantation

­ harmacokinetics of propofol and remifentanil are not signifip cantly altered in chronic kidney disease.

Immunosuppression Immunosuppression strategies aim to prevent graft rejection and form a vital part in the management of renal transplant patients. Immunosuppression regimens vary in different centres, but have traditionally consisted of triple therapy with a calcineurin inhibitor (e.g. ciclosporin, tacrolimus), an antiproliferative agent (e.g. azathioprine, mycophenolate, mofetil) and a corticosteroid. Current regimens adopt a steroid-sparing and calcineurin inhibitor minimization approach. In our centre, the primary immunosuppression strategy includes induction therapy with two 20 mg doses of basiliximab (an interleukin 2 receptor-blocking monoclonal antibody), as advised by the National Institute for Health and Clinical Excellence, the first dose of which is given at induction of anaesthesia, followed by tacrolimus monotherapy. There is, however, a significant shift towards dual agent maintenance immunosuppression in a large number of patients. Different strategies are adopted for patients who are perceived to have a higher risk of rejection (recipients from non-heart-beating donors, previous failed transplant) or those with delayed graft function postoperatively. In these cases, a traditional triple-­therapy or dual-therapy approach is usually adopted.

Muscle relaxants Use of cis-atracurium or atracurium is advocated as they have an organ-independent elimination pathway (Hofmann degradation and ester hydrolysis). Vecuronium and rocuronium can cause prolonged neuromuscular blockade, especially with repeated doses, and should be used cautiously. Interpatient variability is increased in patients with ERF. Sugammadex, a modified gamma cyclodextrin which binds steroid-based neuromuscular-blocking agents, has been shown to provide effective (time to recovery 2.0 minutes vs 1.65 minutes in renal vs control patients) and complete reversal of rocuronium blockade in patients with renal impairment. However, further studies are awaited on the safety and efficacy of this drug in patients with ERF.2 Fluid management and graft optimization Intraoperative volume expansion increases renal blood flow and improves graft function. Most patients are hypovolaemic on induction owing to recent dialysis and fluid removal. It is important to maintain a mean arterial pressure at 70–80 mm Hg to optimize graft perfusion. The central venous pressure is maintained between 10 and 12 mmHg. Normal saline was the crystalloid of choice, but recent concerns over the impaired ability to excrete large amounts of sodium immediately postoperatively, leading to volume overload and the development of hyperchloraemic acidosis following administration of large volumes of normal saline, have led to balanced salt solutions (e.g. compound sodium lactate) being favoured.3 Colloid solutions containing gelatine are used to maintain graft perfusion and avoid hypotension. Fluids containing hydroxyethyl starch have adverse effects on renal function in transplant recipients.4 Prior to revascularization, 1 g of methylprednisolone is given to prevent hyperacute rejection and mannitol (0.5–1.0 g/kg) as a free radical scavenger and osmotic diuretic. Mannitol can cause a rise in serum potassium.

Living-donor kidney transplants Living-donor kidney transplants now represent over 30% of the total kidney transplant programme. The main benefits over deceased-donor transplantation include over 95% primary graft function, shorter waiting times, planned elective surgery and better patient and graft survival. Living donors are usually blood relatives of the recipient; however, there has been an increasing awareness that outcomes from living genetically unrelated donors (partners/spouses) are equal to traditional genetically related donations. In 2006, two new forms of kidney donation were introduced. Altruistic non-directed donation allows an individual to donate a kidney to a stranger via the national matching and allocation system. Paired/pooled donation pairs an incompatible donor/recipient couple anonymously with another ­couple in the same situation in another centre in order to exchange suitably matched organs between couples. Simultaneous donor operations are performed with direct telephonic contact between the two centres with the donor kidney being sent to the centre where the compatible recipient is transplanted. All living donors must make a voluntary and informed decision. The donor is given the option to withdraw at any time. All potential donors and recipients receive individual counselling from an independent healthcare professional. Medical assessment of the potential donor is extensive and is carried out by a clinician who is not part of the transplant team. An independent assessor also assesses the donor to ensure a totally altruistic donation. Particular attention is paid to renal anatomy and function. GFR is measured isotopically with chromium ethylene diamine tetra-acetic acid. In order to determine that the donor in his/her lifetime will not develop clinically significant renal impairment as a result of unilateral nephrectomy, the donor must have sufficient kidney function prior to donation to have an effective GFR at the age of 80 years, independent of the age at which he/she donated. Guidelines of acceptable GFR by age have been produced that will

Analgesia Intraoperative analgesia is maintained either by intermittent boluses of fentanyl or by a remifentanil infusion. The pharmacokinetics of short-acting opioids (e.g. fentanyl, alfentanil and remifentanil) is unaltered in ERF. They do not produce active metabolites. Morphine, conversely, does have an active metabolite (morphine-6-glucuronide) and can have a prolonged mode of action, especially with repetitive dosing. In our centre, therefore, morphine is avoided postoperatively and fentanyl patientcontrolled analgesia (PCA) pumps are used to manage pain. Non-steroidal anti-inflammatory drugs (NSAIDs) are avoided to prevent renal impairment and hyperkalaemia. Acetaminophen (paracetamol) is safe to use in the perioperative period without dose adjustment. Postoperative care Postoperative care should be on a ward staffed by nurses and clinicians with specialist expertise. The aim is to continue to optimize patient well-being and graft function using protocol-driven regimens encompassing fluids, pain relief and immunosuppression management.

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leave a GFR of 37.5 ml/min/1.73 m2 at the age of 80.5 Absolute contraindications for kidney donation include diabetes mellitus, malignancy and hypertension with evidence of end-stage organ damage. Donors with mild hypertension on a single antihypertensive drug are being considered. Other situations where potential donors may be deemed unsuitable include obesity and old age. The assessment of the recipient is similar to assessment for non-living kidney donor transplantation. The living-donor recipients often receive their transplant earlier in the course of their disease, sometimes before dialysis. Thus, although they may have fewer associated co-morbidities, they are more likely to develop hyperkalaemia in the perioperative period. Ideally, the donor kidney nephrectomy and kidney transplant are performed simultaneously in neighbouring theatres in order to minimize the ischaemic time of the kidney. However, it is now generally agreed that there are advantages to both operations being performed sequentially by the same anaesthetic and surgical team. The short increase in ischaemic time has no demonstrable effect on outcome. The donor kidney nephrectomy is performed either laparoscopically or as an open procedure in the partial or full lateral with a lumbar break. The laparoscopic nephrectomy takes longer to perform but causes less tissue trauma and is associated with less postoperative pain and shorter recovery and hospital stay time. Both approaches have similar complication rates (1–2%). Donors are hydrated with 1–2 litres of crystalloid from the night before surgery. General anaesthesia is the method of choice, often combined with an epidural in open procedures. Invasive arterial blood pressure monitoring is recommended as haemorrhage (0.15–0.45%) and cardiovascular instability following major vascular haemorrhage is a potential complication. The donor kidney must be kept well perfused during its retrieval. A positive fluid balance is maintained up to 10 ml/kg/h over surgical losses, especially in laparoscopic nephrectomy, to counteract the compressive effects of the pneumoperitoneum. Urine output should be at least 1.5–2 ml/kg/h. Mannitol (0.5–1.0 g/kg) is given prior to kidney retrieval. Postoperative analgesia is provided with an epidural or PCA combined with abdominal field blocks. There may be a short period of decreased renal function in donors, which prompts some centres to use a fentanyl PCA and avoid NSAIDs. The mortality from donor nephrectomy is 1:3000, with an incidence of wound pain of 3.2%. Kidney transplantation is a life-changing procedure in a group of patients who often have multisystem co-morbidities. Perioperative management of these patients for transplantation and related procedures can be challenging. Although it necessitates lifelong immunosuppression with associated side effects, and in

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spite of the possibility of organ rejection and adverse outcomes leading from this, it still is the most definitive form of RRT and significantly improves the recipient’s quality of life. ◆

References 1 Mazze RI, Callan CM, Galvez ST, et al. The effects of sevoflurane on serum creatinine and blood urea nitrogen concentrations: a retrospective, twenty two center, and comparative evaluation of renal function in adult surgical patients. Anesth Analg 2000; 90: 683–8. 2 Staals LM, Snoeck MMJ, Driessen JJ, et al. Multicentre parallel group, comparative trial evaluating the efficacy and safety of sugammadex in patients with end stage renal failure or normal renal function. Br J Anaesth 2008; 101: 492–7. 3 Jankovic Z, Sri-Chandana C. Anaesthesia for renal transplant: recent developments and recommendations. Curr Anaesth Crit Care 2008; 19: 247–53. 4 Craig RG, Hunter JM. Recent developments in the perioperative management of adult patients with chronic kidney disease. Br J Anaesth 2008; 101: 296–310. 5 British Transplantation Society. The Renal Association. United Kingdom Guidelines for living donor kidney transplantation. Also available at: www.bts.org.uk (accessed 10 Nov 2008).

Further reading Jankovic Z. Anaesthesia for living-donor renal transplant. Curr Anaesth Crit Care 2008; 19: 175–80. Older P, Hall A. Symposium on anaesthesia: preoperative evaluation of cardiac risk. Br J Hosp Med 2005; 66: 452–57. Rela M, Jassem W. Transplantation from non-heart-beating donors. Transplant Proc 2007; 39: 726–72. UK Transplant. Also available at: http://uktransplant.org.uk/ukt/default.jsp (accessed 15 Oct 2008).

Acknowledgements We thank Titus Augustine (Consultant Trasplant Surgeon, M­anchester Royal Infirmary, UK) for his help in the preparation of the article.

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