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Principles of Transplantation Surgery
Introduction
Organ transplantation is the optimal treatment for end-stage organ failure and has the potential to both improve the quality of life and prolong life. It can now be considered for patients with kidney, liver, heart, lung and intestinal failure, as well as for patients with diabetes and bone marrow failure. While the availability and long-term outcomes of transplantation have significantly improved in recent years, this remains an area of intense research and clinical development.
The scene for clinical organ transplantation was set early in the 20th century by Alexis Carrel. He was awarded the Nobel Prize for Physiology and Medicine in 1912, for his pioneering work in vascular surgery and transplantation, with Charles Guthrie. Carrel, working with laboratory animals, found that autografts (organs removed and reimplanted into the same animal) could be expected to function indefinitely, whereas allografts (organs transplanted between animals of the same species) rarely functioned for more than a few days. Early attempts at transplantation in man used xenografts (transplantation between different species) to transfer renal tissue from pigs, goats, rabbits and apes; these were uniformly unsuccessful.
The first clinically useful transplant for humans involved pig heart valves. These consisted of simple avascular tissue, treated to render it nonimmunogenic to avoid rejection. Porcine cardiac valve transplants have been used regularly since the mid-1970s and have advantages over artificial valves in younger people and where anticoagulation must be avoided. The first successful ‘solid organ’ transplant was a kidney transplanted from a living donor to his genetically identical twin, by Joseph E Murray in 1954. The key to organ transplantation between nonidentical twins lay in the developing field of immunology, first with detection of the mechanisms involved in graft rejection and then the elaboration and application of techniques to minimise or prevent it.
Pharmacological immunosuppression designed to attenuate graft rejection has continued to advance, leading to improving success rates with transplantation of an expanding range of organs and tissues ( Table 14.1 ). Human cornea, kidney, liver, pancreas, heart, heart and lung, single or double lung and bone marrow transplantation are all now standard, although not free of rejection or other complications (see http://www.ctstransplant.org/ ). Promising results are also achieved with small bowel transplantation, in isolation or together with other intraabdominal organs, such as stomach, duodenum, pancreas and liver in multivisceral transplants . Even limb, face and uterus transplants are now achieving success.
TABLE 14.1
Summary of the Main Immunosuppressive Agents Used in Transplantation
| Class of Drug | Examples | Mechanism of Action | USES | Adverse Effects and Comments | ||
|---|---|---|---|---|---|---|
| Induction | Maintenance | Rejection | ||||
| Biological Agents | ||||||
| Non-depleting antibodies | Basiliximab | Inhibition of IL2-induced T cell activation (mAb) | √ | Hypersensitivity and adverse effects are rare | ||
| Depleting antibodies | Alemtuzumab (Campath-1H) | Prolonged depletion of B and T lymphocytes (mAb) | √ | Cause moderate cytokine release syndrome | ||
| ATG (antithymocyte globulin) | Prolonged depletion of T lymphocytes (polyclonal Ab) | √ | √ | Cytokine release syndrome common | ||
| Rituximab | Depletion of B lymphocytes (mAb) | √ | √ | Not formally licensed for use in transplantation | ||
| Nonbiological Drugs | ||||||
| Calcineurin inhibitors (CNIs) | Ciclosporin | Inhibition of calcineurin phosphatase and T cell activation | √ | Nephrotoxicity is a significant adverse effect | ||
| Tacrolimus | √ | |||||
| mTOR a inhibitors | Sirolimus (rapamycin) | Inhibits IL2-induced T cell proliferation | √ | Cause impaired wound healing, pneumonitis | ||
| Antimetabolites | Mycophenolate mofetil (MMF) | Suppression of B and T cell proliferation | √ | Myelotoxicity (pancytopenia) and GI disturbance common | ||
| Azathioprine | Inhibition of DNA synthesis in lymphocytes | √ | In general, well tolerated | |||
| Corticosteroids | Prednisolone (PO) | Suppression of cytokine production, T cell activation and migration | √ | Cause the full spectrum of Cushing syndrome adverse effects | ||
| Methylprednisolone (IV) | √ | √ | ||||
a DNA, Deoxyribonucleic acid; GI, gastrointestinal; IL2, interleukin-2; IV, intravenous; mAb, monoclonal antibody; mTOR, mammalian target of rapamycin; PO, orally.
Transplant Immunology
Major Histocompatibility Complex
When transplanted from one individual to another, nucleated cells have a number of different surface glycoproteins known as histocompatibility antigens that are recognised by the recipient’s immune system as foreign and elicit a response. The immune response involves cell- and antibody-mediated mechanisms, which cause destruction of the transplanted cells.
Each individual has several histocompatibility antigens, but one group is predominantly responsible for 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 . Two major groups of HLA 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, B and C antigens and the principal class II loci are the DP, DR and DQ antigens .
Tissue Typing and Organ Allocation Schemes
ABO blood group compatibility is an obvious prerequisite for organ transplantation. Allocation of organs to recipients further involves determining the donor and recipient HLA haplotypes (‘HLA typing’). This is done by detecting genetic variation in the expressed HLA molecules using antisera (serological typing), or now almost universally, at deoxyribonucleic acid (DNA) sequence level (DNA typing). The antigens at HLA A, B and DR loci are particularly important determinants of the immune response to transplanted organs. Since each individual receives one set of genetic information from each parent, there are six principal loci, and any two individuals can differ at any or all of these loci.
In kidney transplantation, close HLA matching gives significantly better graft survival. HLA typing of individuals is therefore used to match the donor and recipient as closely as possible in kidney (and pancreas) transplantation. HLA matching is not currently regularly performed for other organs, such as heart or liver transplants, as the number of available organs is too small to allow optimal matching. However, even a fully HLA matched transplant evokes a profound immunological response from the recipient because of differences in other major (non-A, non-B and non-DR) and minor histocompatibility antigens. Immunosuppression is therefore a prerequisite for successful organ transplantation.
Most developed countries have a national transplant sharing mechanism so that donors and recipients can be matched as closely and fairly as possible. Systems are designed to achieve an optimal balance between utility (the optimum use of an organ in terms of graft survival) and equity of access (the chance that an individual patient will receive a graft within a reasonable period). This typically combines the important matter of tissue matching with other factors, such as age and time spent on the waiting list.
Immunosuppression
Immunosuppressive therapy needs to be continued indefinitely after transplantation, although the 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 nonbiological agents; the characteristics of the main examples are summarized in Table 14.1 . Immunosuppressive drugs are almost always used in combination to allow lower doses of individual agents to minimise side-effects. These adverse effects include infections, impaired wound healing, predisposition to certain malignancies (e.g., skin and lymphoproliferative disorders) and bone marrow suppression. A widely used combination is induction with basiliximab , followed by maintenance on prednisolone , tacrolimus and mycofenolate mofetil.
Graft Rejection
Graft rejection continues to be a problem despite improved efficacy of immunosuppressive agents. It can present in several ways:
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