Major histocompatibility complex

When transplanted from one individual to another, tissue cells have a number of different surface glycoproteins known as histocompatibility antigens that are recognised by the recipient’s immune system and excite a response. The response involves cell-mediated and humoral mechanisms which cause destruction of the transplanted cells.

Each individual has several histocompatibility antigens, but one group is predominantly responsible for major graft rejection. These major histocompatibility antigens are coded for by a set of genes known as the major histocompatibility complex (MHC). In humans, the MHC gene is located on a segment of the short arm of chromosome 6. It was first discovered in leucocytes and, although now shown to be present in all cells, it is still known as the human leucocyte antigen (HLA) complex. Within the human MHC, two major groups of antigens, known as HLA class I and class II, have been described, each with different structures and specificities. The principal class I loci are the A and B antigens and the principal class II loci are the DR antigens. Since each individual receives one set of genetic information from each parent, there are six principal loci (two each for A, B and DR) and any two individuals can differ at any or all of these loci. Certain HLA types are also associated with particular autoimmune disorders, notably ankylosing spondylitis and coeliac disease, although the reason is unknown.

Immunosuppression

With any major organ transplant, the recipient’s immune response must be suppressed, even with full HLA compatibility, so rejection and graft loss can be minimised. Immunosuppressive therapy needs to be continued indefinitely, although dosage can usually be progressively reduced to maintenance levels after high-dose induction therapy. This is because a partly tolerant state is established by diminution of the alloimmune response with time. Episodes of rejection are often treated with strong or high-dose immunosuppression.

Immunosuppressant drugs are broadly classified into biological (monoclonal or polyclonal antibodies) and non-biological agents; the characteristics of the main examples are summarized in Table 14.1. Immunosuppressive drugs are almost always employed in combination to allow lower doses of individual agents to minimise side-effects. These include infections, impaired wound healing, predisposition to certain malignancies (e.g., skin and Epstein–Barr virus-related lymphoproliferative disorders) and bone marrow suppression. A widely used combination is induction with basiliximab, followed by maintenance on prednisolone, tacrolimus and MMF.

Sources of organs for transplantation

Organs for transplantation may be procured from living or deceased donors. Deceased donation in the UK can proceed after ‘brain death’ (donation after brain death—DBD or ‘heart-beating’) or after ‘circulatory death’ (donation after circulatory death—DCD or ‘non-heart-beating’). Whilst the number of organ transplants from living donors (LD) and DCD donors has increased in the UK over recent years, there has been a slow decline in DBD donors. Consent for deceased organ donation can be given by the donor during his/her lifetime by registration with the Organ Donor Register, or by the donor’s next of kin immediately before death (in the case of a DCD donor) or after the diagnosis of brainstem death (DBD donor).

‘Brain death’

In many countries, criteria have been established for a legal definition of brain death following irreversible brainstem injury (e.g. from head injury or intracranial vascular catastrophe), even in the presence of an intact circulatory system. Once the established criteria have been satisfied and appropriate consent obtained from relatives, the subject becomes eligible for DBD donation and the organ retrieval operation can proceed with the donor ventilated and the organs perfused with oxygenated blood. If brainstem death has not occurred or cannot be confirmed, ventilatory and circulatory support is withdrawn and organ retrieval can only proceed after circulatory arrest and death confirmed by irreversible cessation of neurological (pupillary), cardiac and respiratory activity (DCD donation). These are donor patients with a hopeless prognosis and treatment is withdrawn in an intensive care setting.

The legal criteria for brain death in the UK are summarised in Box 14.1; similar criteria are used in other countries. In the UK, the diagnosis of brain death is made on purely clinical criteria; electrocardiography, cerebral blood flow and other neurophysiological tests are not required. Appropriate clinical examination must be performed by two senior doctors independent of the transplant team and must be repeated at least twice.

Living donation

UK law permits kidney transplants from living genetically or emotionally related as well as from altruistic donors. This can only proceed after comprehensive medical and psychological assessment of the donor. Living donor nephrectomy can be performed laparoscopically or through an open (usually retroperitoneal) surgical approach. Laparoscopic nephrectomy results in less wound pain, shorter hospital stay and shorter rehabilitation for the donor. The advantages of living donor transplantation include elective not emergency procedures, better long-term graft outcomes, lower delayed graft function rates, and potentially, pre-emptive (pre-dialysis) transplantation. Living kidney donation has a mortality risk of 1 : 3000 and a major and minor complication rate of approximately 2% and 20% respectively in the donor.

Living livers donation is also becoming more common. It was introduced to allow donation of a small portion of the left liver from parent to child, but has now expanded to include right liver donation, and allows adult to adult transplantation. The donor risks are greater than in kidney donation. In countries where the availability of cadaveric organs is limited for cultural reasons, such as Japan, these procedures are the mainstay of organ transplantation. The growing shortage of organs for transplantation has led to this being adopted even in countries where cadaveric liver transplantation is well established.

Organ preservation and transport

Donors are often in hospitals many miles from where the recipient operation is to be performed. There may be delay in locating the recipient, and in getting the recipient into hospital and ready for operation. As a result, the organ to be transplanted is usually removed from the donor several hours before transplantation, driving the search for reliable techniques of organ preservation. Hypothermia (at 0–4°C) is the main method of organ preservation by reducing the metabolic demands of the organ. Organs are first flushed with and then stored in preservation solutions which usually have the following components:

After retrieval, the bag containing the organ and preservation fluid is usually packed in ice (static cold storage) while awaiting transplantation. Alternatively, kidneys may be connected to a machine to continuously circulate cold preservation solution (machine perfusion). Machine perfusion is more expensive and cumbersome than static cold storage; its potential advantages include a more physiological environment and the ability to identify and discard non-functioning kidneys with poor perfusion characteristics.

The period of warm ischaemia is the time from circulatory arrest to effective cooling of the organ. Warm ischaemia must be minimised to prevent irreversible damage to the organ (less than 40–60 min in kidney transplantation). The period of cold ischaemia is from perfusion with cold preservation solution to transplantation. Cold ischaemia time should also be minimized to best preserve graft function and ideally should be less than 24, 12 and 6 hours for kidney, liver and heart transplantation respectively.

Kidney transplants

Kidney transplantation is the longest established and most widely practised of solid organ transplants. It offers a substantial improvement in quality of life for patients with end-stage chronic renal failure who are otherwise faced with twice- or thrice-weekly haemodialysis or a regimen of daily treatment with chronic ambulatory peritoneal dialysis. Donor organs can be obtained from any generally healthy donor up to 70 years of age or even older in certain cases.

The kidney is transplanted into an extraperitoneal location in the iliac fossa and the renal vessels anastomosed to the iliac artery and vein (see Fig. 14.1). The ureter is implanted into the bladder using an intramural tunnel to prevent reflux. Non-functioning kidneys are usually left in situ unless infected or causing unmanageable hypertension.

The signs of early acute rejection of the kidney are oliguria, proteinuria, and pain and tenderness of the transplanted kidney. Luckily, this relatively common form of rejection can be usually be reversed easily. Overall results have steadily improved owing to better tissue matching, more effective and safer immunosuppression, superior organ procurement and preservation, as well as improved surgical technique and perioperative care of recipients. The survival rate of transplanted kidneys can be as high as 90–95% at 1 year and falls to about 50% at 10 years.

Liver transplants

Current indications for liver transplantation in adults are end-stage non-malignant parenchymal liver disease (e.g. cirrhosis due to viral hepatitis or alcohol), acute hepatic failure, certain inborn errors of hepatic metabolism and hepatocellular carcinoma (within specific criteria). In children, liver-based inborn errors of metabolism and biliary atresia are the most common indications; the operation often needs to be performed during early infancy.

Rejection in liver transplantation is less of a problem than in kidney transplantation but the operation is more challenging. Most patients have advanced liver disease with disordered coagulation and often severe portal hypertension. A team approach has evolved, with close cooperation between surgeons and specialist anaesthetists. The diseased liver is removed and the new liver placed orthotopically, with vena cava, portal vein and hepatic artery being re-anastomosed in turn. Biliary reconstruction can be performed using a direct duct-to-duct anastomosis or a Roux-en-Y loop. Results have improved greatly since the first liver transplant in 1963 and 1-year patient survival rates of 85–90% and 5-year survival of 70–75% are now standard. For paediatric cases, the problem of an insufficient supply of donor organs has been solved with reduced-size liver grafts. An adult liver can be divided into two to allow a child and an adult to receive grafts from a single organ. The late graft attrition rate appears to be much lower than for kidney grafts even though matching is by blood group without tissue typing. Biliary complications (e.g. strictures) and disease recurrence, particularly when transplantation is for hepatitis C, are important remaining challenges.

Pancreas transplants

Pancreas transplantation offers the tantalising hope of a cure for diabetes, thus avoiding its many late complications. These include myocardial ischaemia, peripheral vascular disease, peripheral neuropathy, nephropathy leading to renal failure and retinopathy leading to blindness. The pancreas presents particular problems, as the gland combines endocrine and exocrine function. The currently favoured technique involves transplanting the whole pancreas with a small segment of duodenum. The graft is sited in the pelvis and its vessels are anastomosed to the iliac vessels as in a kidney graft. In an early technique, the attached duodenal segment was anastomosed to the bladder, allowing exocrine secretions to drain into the urine. This has been largely replaced by anastomosing the pancreas directly to small bowel or via a Roux-en-Y loop to allow enteric drainage of enzymes. Graft survival rates of 70–80% are now being obtained and there is increasing evidence that the procedure can arrest and sometimes partly reverse the long-term complications of diabetes. Most pancreatic transplants currently performed are in diabetic patients with renal failure and advanced complications of their disease. In these, the pancreatic transplant is performed together with a renal transplant (simultaneous pancreas and kidney transplant—SPK).

A different approach is transplanting pancreatic endocrine tissue alone using human islet cells extracted from pancreases by collagenase digestion. The islets are injected into the portal venous system and lodge in liver sinusoids. The extraction yield has improved markedly, allowing a substantial proportion of islets to be recovered from each pancreas. Whilst the success rate is improving, it requires islet cells from more than one donor to achieve euglycaemia, so the procedure is less efficacious than whole pancreas transplantation while organ donors remain scarce.

Heart and lung transplants

Cardiac transplantation has become a standard treatment for patients with ischaemic heart disease not amenable to coronary artery bypass grafting, and for patients with certain cardiomyopathies. A standard operative technique employs orthotopic placement, i.e. replacing the diseased organ in the same anatomical location. The donor atria and vessels are sutured directly to those of the recipient. Monitoring for early rejection requires regular right-heart catheterisation and endomyocardial biopsy.

Using immunosuppressive protocols similar to kidney transplantation, results of cardiac transplantation are now excellent, although the shortage of donor organs means cardiac transplantation is unlikely ever to be an option for all those who could benefit.

Combined heart and lung transplants are now accepted as a standard treatment for certain irreversible lung diseases such as cystic fibrosis, and good results are now obtained in specialist centres. Many cases have secondary heart disease and require a combined heart–lung transplant. In other cases the recipient’s heart is healthy and can be transplanted into another patient; this is known as the domino heart procedure. Single or even double lung transplants are now also performed successfully in carefully selected patients with chronic respiratory failure.

Small bowel transplants

Small bowel transplantation is a relatively recent advance. There is a growing number of patients who have lost all or most of their small bowel from vascular problems, volvulus, necrotising enterocolitis, atresias or Crohn’s disease, and who are maintained on long-term parenteral nutrition. Specialist units can sustain them in good health for years but treatment is expensive, inconvenient for patients and leaves them at constant risk of infective and thrombotic complications from feeding lines as well as liver disease from parenteral feeding. Small bowel may be transplanted alone or combined with the liver in coexisting irreversible liver disease. Outcomes have improved significantly so that in selected cases, small bowel transplantation rivals long-term total parenteral nutrition in survival and has clear advantages in quality of life.