Transplantation is the replacement of a diseased organ with a healthy one. The concept of transplantation as a means of treating end-stage organ failure has intrigued surgeons for centuries, but has become a therapeutic reality only within the last 50 years. During that time, enormous advances have been made, including the discovery of powerful immunosuppressive drugs, identification of the molecular and cellular events involved in the rejection response, development of organ preservation methods, advances in patient care and management, and evolution of complex surgical techniques for replacement of a wide variety of organs and tissues. Today, transplant operations are fairly routine procedures. The impact of successful transplantation on the lives of recipients is immense and extremely gratifying for those involved in their care.
Allograft rejection is the recipient's normal immune response to an organ or tissue transplanted from another individual (an allograft). It results in damage to the graft and is an inevitable consequence of allotransplantation, unless either the recipient becomes tolerant to the transplanted organ or immunosuppressive therapy prevents the process. Rejection is a highly complex series of sequential and closely interrelated events involving immune cells, cytokines, antibodies, and self-regulatory mechanisms.
Clinical patterns of rejection
Several patterns of rejection are recognised on clinical and histopathological grounds. All are characterised by deterioration of graft function.
Hyperacute rejection occurs within minutes of restoring blood flow to the transplanted organ in the recipient. It is due to pre-formed specific cytotoxic antibodies in the recipient interacting with antigens expressed on the surface of vascular endothelium in the allograft, with subsequent activation of complement and intravascular thrombosis. It is irreversible and results in immediate graft loss. Potential recipients are screened before transplantation for the presence of such antibodies by a dye-exclusion cytotoxic cross-match test in which lymphocytes from the donor are reacted with recipient serum in the presence of a vital dye.
Accelerated acute rejection
Accelerated acute rejection occurs within 2–4 days of transplantation in patients already sensitised to donor antigens (e.g. by previous pregnancy or blood transfusion), and probably involves both cellular and humoral anamnestic responses. It may be reversible with anti-rejection treatment.
Acute rejection is primarily cell-mediated rejection that is first manifest 5–7 days after transplantation in unsensitised recipients. It may occur subsequently at any time(e.g. if immunosuppressive therapy is stopped many months after transplantation). It is usually reversible with anti-rejection treatment.
Chronic rejection occurs months or years after transplantation. Deterioration in graft function is slow. Histological features include progressive obliterative arteritis and interstitial cellular infiltration and fibrosis. The pathogenesis is poorly understood and there is no specific treatment. It is the most common type of rejection leading to loss of organ transplants.
Immunosuppressive drugs were first used in clinical transplantation in the late 1950s, and are used to prevent and treat acute rejection. Different immunosuppressive strategies and agents are used depending on the transplanted organ, occurrence of side effects, strength of the rejection response, and experience and preference of the treating clinicians. Currently, flexible combinations of prednisolone, mycophenolate, and cyclosporine or tacrolimus are the most widely used maintenance immunosuppressive regimens in solid organ transplantation. In addition, some transplant programs use anti-T cell monoclonal antibodies as ‘induction therapy’ for the first few days after transplantation. Acute rejection is treated with high-dose prednisolone, monoclonal antibodies or switching to a different immunosuppressive regime. Suppression of the immune system to the extent that allograft rejection is prevented has two major consequences: infection and malignant disease.
Infection is the commonest complication of immunosuppression and the commonest cause of morbidity and mortality after transplantation. Immunosuppressed patients are particularly at risk for infections that normally are eliminated by cell-mediated immune mechanisms.Within the first few weeks after transplantation, most infections are related to the surgical procedure and are usually bacterial in nature (e.g. infections of the chest, wound, intravenous lines, drain sites, urinary tract). After 1–2 months, infections are most frequently opportunistic, and can be viral (cytomegalic, herpes simplex, varicella zoster, Epstein-Barr), fungal (candida, aspergillus, cryptococcus), protozoal (Pneumocystis carinii, toxoplasmosis) or bacterial (Listeria, Mycobacterium, Legionella, Nocardia).
Nearly all types of cancer are more common in immunosuppressed transplant recipients. Although not elucidated fully, the reasons include reduced immune surveillance of potentially neoplastic cells, infection with oncogenic viruses, prolonged antigenic stimulation of the lymphoreticular system by the allograft and, very rarely, transfer of malignant cells with the allograft. The risk for developing cancer after transplantation increases with time, especially in cancers related to environmental factors, and the overall lifetime relative risk (RR) of a transplant recipient developing cancer is approximately three times that of the general population. The most frequently observed common cancers in long-standing kidney transplant recipients are nonpigmented skin cancers (RR = 200), non-Hodgkin's lymphoma (RR = 20), cancers of the urinary tract (RR = 5), and carcinoma of the female genital tract (RR = 3). Cancers which are unusual in the general population but have a high RR in renal transplant patients include Kaposi's sarcoma (RR = 1000), lymphoma of the central nervous system (RR = 1000), thyroid cancer (RR = 300), and carcinoma of the vulva and vagina (RR = 35). Generally, malignant diseases in transplant recipients appear earlier, grow more rapidly, and metastasise earlier than in the general population.
Transplantation is entirely dependent on organs either donated by living donors or obtained from deceased donors with the permission of the next of kin.
A person may donate an organ to another individual with end-stage organ failure if the donor and recipient blood groups are compatible, the recipient does not have cytotoxic antibodies directed against donor MHC antigens, and the donor is medically and psychologically suitable. Living donors are the only source of transplant organs in countries where cadaver organ donation is not accepted. Use of living donors has increased considerably over the last 10 years because of the great shortage of deceased donor organs. Live organ donation is restricted largely to kidneys and bone marrow, although recently living donor liver, pancreas, small intestine, and even lung transplants have been performed.
Organs may be obtained from three groups of living donors.
- Living related donor - donor and recipient are biologically related (e.g. parent to offspring). Such donations currently account for 38% of kidney transplants performed in Australia.
- Living unrelated, altruistic donor - donation to a genetically unrelated but legally or emotionally related individual for altruistic reasons (e.g. husband to wife, friend to friend). About 4% of transplanted kidneys in Australia come from this source.
- Living unrelated, paid donor - donation of an organ for material gain (e.g. selling a kidney to someone with renal failure through an organ broker). Paid organ donation is regarded as unethical in many developed nations (including Australia), but is practised illegally in some developing countries where other maintenance treatments for end-stage organ failure are unavailable. In such cases, both donor and recipient may be subject to gross exploitation.
Potential live organ donors require extensive investigation to ensure that they are medically fit, that the organ to be donated is healthy, and that the donor will not suffer long-term medical or psychological consequences as a result of donating. Living donor transplant procedures are performed electively, with the donor and recipient operations performed concurrently.
Although a severe worldwide shortage exists of cadaver donors with respect to the number of patients requiring organ transplants, deceased donors provide the majority of organs transplanted in developed nations. Organ donation rates in Australia and New Zealand are amongst the lowest in the developed world, with approximately 10 donors per million population (pmp) annually, while Spain has the highest rate (33 pmp). Cadaver organ donation is not practised in some countries because of the absence of brain death legislation (see below) and for cultural reasons.
The process of deceased donor organ donation
If vital organs are to be removed for transplantation, two criteria must be fulfilled.
- Death of the donor must be diagnosed with certainty.
- Transplanted organs must be in good condition so that they can sustain life within the recipient. This means that, although dead, the donor must have a circulation so that organs to be donated receive an adequate oxygen supply up to the time they are removed.
In practice, deceased donors are ‘brain stem dead’; that is, the vital parts of the brain have died, there is irreversible loss of the capacity for consciousness, and the brain as a whole is incapable of functioning and sustaining life; although other organs (e.g. heart, liver, kidneys) may still function for some time after the brain is dead because the cadaver still has a circulation. Key components of the brain stem and their functions are shown in Table 16, “Functional components of the brainstem”.
|Reticular activating system||Activation of the cerebral cortex|
|Vasomotor centre||Control of heart rate and blood pressure|
|Cortico-spinal tracts||Transmission of all motor output from the brain|
|Spino-thalamic tracts and medial lemnisci||Transmission of all sensory input into the brain except sight and smell|
|Cranial nerve nuclei||Activity of cranial nerves|
Patients admitted to intensive care units in deep coma and requiring ventilatory support because of serious brain injury should be considered as potential organ donors until proven otherwise. The precise cause of coma is determined and treated, and the neurological status is assessed repeatedly. If there is no improvement, brain stem function is assessed formally by performing simple clinical tests at the patient's bedside. The criteria for brain stem death are shown in Clinical criteria for brainstem death. Death is defined by law in Australia, and the law requires (i) the condition of any patient who satisfies the criteria for brain stem death is demonstrably irreversible, and (ii) there is certainty of cessation of brain function. Causes of death amongst deceased organ donors are shown in Table 17, “Causes of death amongst Australian cadaver organ donors (ANZDATA Registry 2003 Report)”.
After certification of death, the cadaver is assessed to determine if contraindications exist to organ donation (e.g. systemic or localised infection, extracerebral malignancy, risk of HIV infection, disease of donor organs). Maintenance of the circulation, ventilation, fluid and electrolyte balance, supportive therapy and nursing care are continued. The next of kin are asked for permission to remove specific organs and tissues for clinical transplantation and/or research purposes. If permission is refused (approximately 35% of requests), further treatment is discontinued. If permission is given, contact is made with the nearest transplant hospital and the transplant coordinator arranges the organ donation. Full supportive treatment is continued. Tissue typing and viral serology, including HIV status, are determined. The coroner's permission is sought when death is suspicious or traumatic. The corpse, still being ventilated, is taken to the operating theatre, and the donated organs are removed by transplant surgeons with the same care, dignity and attention to detail as in any surgical operation. Approximately 80% of cadaver organ donors are multi-organ donors. Organs are allocated to recipients according to strict and well defined criteria.
|Cause of death||%|
Almost all cadaver organ donors die suddenly and unexpectly, a situation which increases the enormous grief and stress experienced by their next of kin. For many families, organ donation allows some good to come from what is otherwise a disastrous and shattering event, as they realise that their loved one's donation may mean a new life for the organ recipients. Organ donation is indeed a unique ‘gift of life’ to recipients.
If organs are to function immediately and sustain life in recipients after transplantation, they must be removed expertly from the donor and treated to minimise ischaemic damage. In deceased donors, the organs are mobilised and surrounded with sterile ice, and their arteries are perfused with cold (4–6°C) preservation solution (in situ perfusion), and again after removal (extracorporeal perfusion). Only extracorporeal perfusion is used in living donor operations.
The perfusion fluid
- Rapidly cools the organs, thereby reducing their metabloism and oxygen requirement.
- Flushes out blood and prevents intra-organ thrombosis.
- Reduces the impact of ischaemic damage.
Preservation solutions contain
- Electrolytes - usually high potassium and low sodium.
- Buffer - e.g. citrate, phosphate, potassium lactobionate.
- Impermeants to reduce cellular oedema and swelling - e.g. mannitol, raffinose.
- Agents designed to reduce ischaemic damage and reperfusion injury - anti-oxidants, enzymatic inhibitors, calcium channel blockers, anti-inflammatories.
After removal from the donor, the organs are placed in sterile plastic bags, which are sealed, placed in a coolbox and surrounded by ice. Organs may be transported to other hospitals, perhaps interstate. Maximum storage times are 30–36 hours for kidneys, 12–20 hours for livers, 10–20 hours for the pancreas, and 4–6 hours for hearts and lungs.
Kidney transplantation was the first clinical transplant discipline and became established with the advent of immunosuppressive therapy in the early 1960s. The kidney is the most frequently transplanted solid organ. Approximately half of the 9,000 patients maintained currently on dialysis in Australia and New Zealand are suitable for kidney transplantation, the remainder being excluded largely because of other serious medical conditions, particularly cardiac and respiratory disease. The need for kidney transplantation is estimated at approximately 40 pmp per year, about four times that of the deceased donor organ donation rate. The current rate of kidney transplants in Australia and New Zealand is 31 pmp.
Living donor nephrectomy is performed usually through a loin incision, or with laparoscopic assistance and a lower abdominal incision. The deceased donor operation involves removal of both kidneys and proximal ureters, together with the abdominal aorta and inferior vena cava. The kidney is transplanted into an iliac fossa, close to the bladder. The renal artery and vein are anastomosed to the respective iliac vessels and the ureter is anastomosed to the side of the bladder (uretero-neocystostomy).
Post-operatively, particular attention is paid to the recipient's urine output, blood pressure, fluid status, renal function and immunosuppression. As with all immunosuppressed patients, infection is a particular concern. Average hospital stay is 7–10 days.
Complications are infrequent but potentially serious because recipients may have had long periods of chronic illness and debility before transplantation and are immunosuppressed. Potential complications include:
- General complications of any operation - wound problems (infection, haematoma, dehiscence, hernia), infections (chest, urine, drip sites), deep vein thrombosis.
- Vascular - transplant renal artery and vein thrombosis, anastomotic bleeding, peri-transplant haematoma, transplant renal artery stenosis.
- Lymphatic - lymphocele.
- Urological - ureteric ischaemia, necrosis, stenosis and obstruction, and urinary fistula.
- Scrotal - oedema, epididymo-orchitis, hydrocele.
- Neurological - damage to ilio-inguinal, genitofemoral and femoral nerves.
- Allograft rejection.
- Recurrent disease in the transplant - diabetic nephropathy, focal segmental hyalinosis, metabolic causes of renal failure.
One- and 5-year patient and kidney survival rates are shown in Table 18, “Patient and graft survival after transplantation”. Of 16,270 kidney transplants performed in Australia and New Zealand during the 40-year period 1963–2002, 6854 (42%) are still functioning. Graft survival is significantly better for recipients of living rather than deceased donor renal transplants. The commonest cause of transplant failure is chronic rejection.
|Patient survival (%)||Graft survival (%)|
|Organ||1 year||5 year||1 year||5 year|
|Deceased donor kidney||94||85||91||76|
|Living donor kidney||98||92||94||86|
|Combined intestine and liver||65||30||65||30|
As with other successful solid organ transplants, most renal transplant recipients experience vastly improved health and vitality, are well rehabilitated, and are fit for full-time work. Particular benefits to paediatric recipients are social and developmental rehabilitation and ‘catch-up’ growth in those with growth retardation. Renal transplantation is also the most costeffective treatment for chronic renal failure.
Unlike end-stage renal, pancreatic or intestinal failure, no artificial means of support exists for patients with liver failure, and so patients either die before a liver transplant becomes available or come to transplantation with advanced liver disease and its complications, including jaundice, malabsorption, malnutrition, coagulopathy, cardiomyopathy and pulmonary disease. Liver transplantation is indicated for end-stage cirrhosis (primary parenchymal, cholestatic and vascular disease), acute fulminant hepatic failure, and rare congenital metabolic disorders.
Careful pre-operative evaluation of potential recipients is essential so that the precise diagnosis, absence of malignancy, and prognosis with and without transplantation are known. Recipients and donors are matched for blood-group compatibility, liver size, and negative cytotoxic cross match. A donor liver may be reduced in size by surgical resection or even split to suit two recipients, but these procedures add considerable risk.
The recipient operation is a major undertaking and is often prolonged because of its difficult nature and often the need to perform vascular reconstruction before transplantation. Operation involves (i) establishment of veno-venous bypass via the femoral and axillary veins, (ii) excision of the recipient's liver (hepatectomy), (iii) implantation of the donor liver by anastomosing the donor supra- and infra-hepatic inferior vena cava (IVC), portal vein and hepatic artery to those of the recipient, (iv) biliary reconstruction by anastomosis of the donor common bile duct to the recipient's common bile duct or jejunum, and (v) donor cholecystectomy.
Post-operatively, patients are monitored intensively, with attention to their cardiovascular and fluid status, ventilation, liver function and coagulation, blood loss, prevention of sepsis, and immunosuppressive therapy
Complications include primary non-function, bleeding, hepatic artery and portal vein thrombosis, and biliary tract leakage and obstruction. Primary nonfunction occurs in 1–5% of liver transplants and necessitates urgent re-transplantation. In spite of formidable potential complications, patient survival is approximately 85% at 1 year (Table 18, “Patient and graft survival after transplantation”) and 70% at 10 years, a remarkable result for an otherwise uniformly fatal condition. Liver transplantation is very demanding on hospital resources, surgical expertise and personnel, and is limited to a few centres of excellence.
Cardiac transplantation is performed for irreversible end-stage heart failure when life expectancy without transplantation is less than 50% at 1 year. Underlying disorders in adults include cardiomyopathy (42%), ischaemic heart disease (40%), valvular disease (5%), myocarditis (5%), or chronic rejection of or coronary artery disease in a previous transplant (5%).
Cardiac donors are selected with extreme care because the donor heart must function immediately after transplantation. Donor and recipient should be blood group compatible and cytotoxic cross match negative, and body weights should be within 10–15% of each other.
The recipient is placed on cardiopulmonary bypass and the diseased heart is removed (cardiectomy) by excising the ventricles but preserving the atrial septum and most of each atrium. The right and left atria of the donor heart are sutured to the respective recipient atrial remnants, and the pulmonary artery and aorta are anastomosed to their respective vessels. Cardiac rhythm is restored when the coronary arteries are reperfused with blood.
Post-operatively, cardiac pacing, careful intravascular volume loading, inotrope infusion and ventilatory support are required, in addition to intensive immunosuppression and antiviral prophylaxis. Electrocardiography and endomyocardial biopsy are performed frequently to detect cardiac rejection.
Early post-operative complications include cardiac failure, arrhythmias, haemorrhage, tamponade, and infections. Most patients experience one or more episodes of acute rejection within a few months of transplantation, often in the absence of clinical features. Accelerated transplant coronary artery disease occurs commonly after transplantation and is the leading cause of death after the third post-transplant ear, and is the reason for most cases of retransplantation. One- and 5-year survival rates are shown in Table 18, “Patient and graft survival after transplantation”. Rehabilitation after successful transplantation is generally good, with 80% of survivors being restored to their pre-illness level of function.
Lung transplantation is undertaken for end-stage parenchymal or vascular lung disease in patients with poor life expectancy and quality when there is no alternative effective therapy.
Suitable lung donors are scarce because prolonged donor artificial ventilation often leads to pulmonary infection. Recently, living donors have been used occasionally for donation of the right or left lower lobe.
In single lung transplantation, the diseased lung is excised, and anastomoses are made between the donor and recipient left atria, pulmonary artery, and bronchus or tracheae. Double lung transplants require cardiopulmonary bypass, removal of both lungs, and anastomoses between the donor and recipient main bronchi, pulmonary arteries and left atria.
Post-operatively, patients require positive endexpiratory pressure ventilation, careful fluid management to avoid pulmonary oedema, antibiotics, anti-viral and anti-fungal prophylaxis, and intensive immunosuppression. Operative mortality is 10–15%. Subsequently, lung function is monitored closely with regular pulmonary function tests. Bronchoalveolar lavage and transbronchial biopsy are performed whenever rejection is suspected. Potential complications include airway anastomotic dehiscence, atelectasis and infections, and chronic rejection manifesting as obliterative bronchiolitis.
In spite of the poor condition of patients requiring lung transplantation, the enormity of the surgery, and the formidable potential complications, 1- and 5-year survival rates are 80% and 50% respectively for unilateral and bilateral single lung transplants (Table 18, “Patient and graft survival after transplantation”). The majority of patients have dramatic improvement in lung function.
Heart-lung transplantation (HLT) is performed for end-stage primary pulmonary hypertension, congenital heart disease with Eisenmenger's syndrome, and lung diseases causing cor pulmonale, in patients with very limited life expectancy.
Some centres performHLT for parenchymal lung disease and pulmonary hypertension in the presence of a healthy heart, rather than lung transplantation, which is associated with problematic bronchial anastomotic healing. In these cases, the healthy heart of the HLT recipient can be transplanted to a second recipient in need of a heart transplant (domino operation).
Survival rates (Table 18, “Patient and graft survival after transplantation”) reflect the severity of the surgical procedure and the potential for serious postoperative problems with the heart in addition to the lungs.
Pancreas transplantation provides insulin-producing islet tissue, thereby restoring physiological insulin secretion and carbohydrate metabolism, and reducing the progression of microvascular complications. It involves transplanting either a large number of islets as free grafts or the whole pancreas as a vascularised graft, and usually is performed late in the course of insulindependent diabetes mellitus, in long-standing diabetics who also require a kidney transplant because of diabetic nephropathy.
The advantage of islet transplantation is that only insulin-secreting tissue is transplanted, thereby eliminating a major source of post-operative morbidity associated with the unwanted exocrine pancreas. Transplantation of islets involves embolisation into the liver through the portal vein by direct injection or percutaneous catheterisation.
Islet transplantation has been hampered by inefficient islet isolation techniques, which are timeconsuming and yield low islet numbers from each donor pancreas. Also, there are no clinically useful markers of vascular insufficiency or rejection other than hyperglycaemia, the appearance of which signifies loss of the whole islet graft. Recently, these problems have been tackled by using multiple donors for a single recipient and transplanting islets with other organs (kidney, liver) and assuming that islet and solid organ rejection occurs concurrently.
Vascularised pancreas transplantation
The whole pancreas, together with the second part of the duodenum (to preserve the blood supply to the head of the pancreas), an aortic patch which includes the origins of the coeliac trunk and the superior mesenteric artery, and the portal and splenic veins are removed from the deceased donor. This tissue block is transplanted into an iliac fossa; the aortic patch and portal vein are anastomosed to the respective iliac vessels, and the second part of the duodenum is joined to either the small intestine or bladder.
Graft pancreatitis, anastomotic leakage, pancreatic fistulas, arterial and venous thrombosis of the graft, and pancreatic rejection are all serious complications and are associated with considerable morbidity and even mortality. Successful transplantation has an immensely beneficial effect on the patient's quality of life but is not life saving, and established complications of diabetes are not reversed, although mild neuropathy may improve and a concomitant kidney transplant may be protected from developing diabetic nephropathy. One-year patient and graft survival rates are 95% and 75%, respectively (Table 18, “Patient and graft survival after transplantation”).
Several hundred intestinal transplants have been performed for irreversible severe intestinal failure due to short bowel syndrome or absorption and motility disorders in patients in whom parenteral nutrition is failing. An intestinal segment may be transplanted alone or in combination with the liver or other abdominal viscera. Results are generally poor (Table 18, “Patient and graft survival after transplantation”) due to graft rejection, sepsis and multi-organ failure.
Free bone autografts or allografts act as matrices within which new bone forms and are used as bone fragments to fill small bony defects or to strengthen bone fusion.
Vascularised autografts (e.g. fibula, rib, iliac crest) are used when a length of anatomically similar bone is required to replace a section of bone lost because of trauma or resection for malignant disease (e.g. jaw reconstruction with iliac crest bone). After successful anastomosis of nutrient vessels, the graft remains viable and heals to adjacent bone.
Skin autografts (skin grafting) are used as split-skin or full-thickness skin grafts to cover skin defects aftertrauma or surgery. Recently, skin has been taken from patients with extensive burns, cultured, and the resulting sheets of keratinocytes used as thin layers of fragile epidermis without a dermis.
Skin allografts are used rarely to provide wound cover where skin loss is so extensive that it cannot be replaced by autografting alone. The allograft allows time for healing of denuded sites, but because skin is highly immunogenic, it is usually rejected and has to be replaced with another allograft or an autograft taken from a re-epithelialised area.
A few cases of hand allotransplantation for uni- and bilateral hand amputees have been technically successful. Generally, intense immunosuppression is required, and graft survival and functional results are problematic.
Future of transplantation
Clinical organ transplantation has an exciting future and is likely to be an expanding area of surgery. Perhaps the most pressing challenge to overcome is the acute organ donor shortage, which currently is the biggest limitation to transplantation. It is imperative that medical and paramedical personnel and the wider community become aware of the need for deceased donor organs, the concept of brain death, and the enormous cost-benefits of successful organ transplantation.
Scientific advances likely to have positive impacts on clinical transplantation are:
- Encapsulated cell systems - cells (e.g. islets, hepatocytes) are encapsulated in selectively permeable membranes which prevent them from coming into contact with immune cells but allow ingress of oxygen and nutrients.
- Gene transfer - in vivo or ex vivo implantation into target cells of new genes and the sequences which regulate their expression (e.g. induction of graft tolerance, delivery of immuno-modulating molecules to the graft or recipient, treatment of genetic inborn errors of metabolism).
- Xenotransplantation - genetic manipulation of donor animals (e.g. pigs) so that organs transplanted to humans are not rejected.
- Artificial organs - used to maintain patients until a donor organ is available or as a permannetly implanted device (e.g. left ventricular assist device, total artificial heart).
- Tissue engineering - implantation of pre-formed biomaterial constructs to treat a functional or anatomical defect (e.g. arterial conduits, breast tissue, bioartificial liver and pancreas, and tissue patches for the intestine, bladder and heart).
- Further elucidation of the immune response and development of specific immunosuppressive agents with the aim of achieving tolerance.
Morris PJ, ed. Kidney Transplantation: Principles and Practice. 5th edn. Philadelphia: WB Saunders Co; 2001.
Ginns LC, Cosimi AB, Morris PJ, eds. Transplantation. Massachusetts: Blackwell Science; 1999.
ANZDATA Registry Report 2003, Australia and New Zealand Dialysis and Transplant Registry. Adelaide, South Australia.Garner JP. Tissue engineering in surgery. Surg J R Coll Surg Edinb Irel. 2004; 2:70-78.