Transplants

Transplantation of organs and tissues has developed rapidly alongside enormous advances in immunology, immunosuppressive therapy (Ch. 19) and medical and surgical technology. Organs and tissues currently transplanted are shown in Table 35.1.

Indications

Transplantation is frequently a life-saving procedure. Solid organ transplants (SOTs) of kidney, liver, heart, lung, pancreas and small bowel are now the treatments of choice for end-stage organ failure with substantial limitation of daily activities and limited life expectancy.

Autografts (autologous transplants) refer to cells that are collected from an individual and given back to that same person (e.g. veins used for coronary artery bypass grafting, skin used for grafts or blood). Autografts are the most common type of transplant used to treat patients with haemopoietic stem-cell transplantation (HSCT; or bone marrow transplantation [BMT]).

Allografts (allogeneic transplants) refers to cells that come from another individual, who may be a relative or not, but the donor’s blood must be closely matched to the recipient’s (more likely when the donor is a sibling).

Isografts are allografts in which organs or tissues are transplanted from a donor to a genetically identical recipient (e.g. an identical twin). Most human tissue and organ transplants are allografts that are not so closely matched, which means that the recipient needs to be immunosuppressed to prevent transplant rejection. Organ donation is crucial to provide adequate material.

HSCT is the transfer of haemopoietic stem cells from one individual to another (allogeneic HSCT), or the return of previously harvested cells to the same individual (autologous HSCT) after manipulation of the cells and/or the recipient. It developed from the infusion of bone marrow cells into patients after prior radio- or chemotherapy and is also widely employed in many neoplastic and autoimmune conditions (Fig. 35.1). Allogeneic HSCT can cure or improve outcomes in a variety of conditions, including leukaemias, lymphomas, myeloproliferative disorders, myelodysplastic syndromes, bone marrow failure syndromes, congenital immunodeficiencies, enzyme deficiencies and haemoglobinopathies.

Best transplant results are in ambulatory patients with rehabilitation potential, who have no other significant co-morbidity, a satisfactory psychosocial profile, an emotional support system and nutritional status. Transplantation may be refused by some Jehovah’s Witnesses and Orthodox Jews.

Peripheral blood stem-cell transplantation (PBSCT) and umbilical cord blood transplantation are also used as sources of haemopoietic stem cells for transplants.

Solid Organ Sources

Transplants can be from live or dead (‘cadaveric’) donors, or from donors who are living but ‘brain-dead’ – a state defined by an irreversible cessation of all brain and brainstem functions; this is determined on clinical criteria during two separate examinations performed 24 hours apart, or by ancillary studies to assess brain activities. An absence of drugs, hypothermia or metabolic derangements must be confirmed. Brain death criteria are shown in Box 35.1. One of the main obstacles to transplantation is the lack of donors (Fig. 35.2).

Transplantation Outcomes

Success for different types of organ transplanted can, in some instances, approach 90% at 1 year, the major barrier to success being immunological rejection. Except for transplants between identical twins, all transplant donors and recipients are immunologically incompatible and host cells attempt to destroy or reject the transplanted organ, which, with time, can lead to graft failure or patient death. The other main cause of graft rejection is patients’ failure to continue taking their immunosuppressive drugs.

To try to avoid transplant rejection, transplant recipients and donors are tissue-typed to determine the human leukocyte antigen (HLA) class I and class II loci; the degree of incompatibility is defined by the number of antigens mismatched at each HLA locus. The degree of humoral sensitization to HLA antigens is also determined; sensitization happens when the recipient has received multiple blood transfusions from a previous organ transplant or during pregnancy. Cross-matching is an in vitro assay to determine whether a potential transplant recipient has preformed anti-HLA class I antibodies against those of the organ donor. A negative cross-match must be obtained before accepting an organ for transplantation. Transplantation of an organ into a recipient sensitized against donor class I HLA antigens puts the recipient at high risk of hyperacute antibody-mediated rejection. ABO blood group determination is used to establish whether the patient is a potential target of recipient circulating preformed cytotoxic anti-ABO antibody. Transplantation across incompatible blood groups may result in a humorally mediated hyperacute rejection.

Prevention of Rejection

Following transplantation, all patients need treatment with immuno-suppressive drugs for life, to prevent T-cell alloimmune rejection. These are discussed in Chapter 19.

Treatment goals are to achieve the highest rates of patient and graft survival, and to minimize toxicity, infections and malignancy. The current high graft survival rate is due to increasingly effective immunosuppression. There is no consensus as to the single best protocol, and each transplant programme uses slightly different regimens.

Induction immunosuppression immediately after transplantation is a short course of intensive treatment to almost abolish the circulating lymphoid cells critical to rejection. Induction agents are given less often if the graft functions immediately, as in recipients of living kidney donors, especially HLA-ID grafts. Maintenance immunosuppression usually uses corticosteroid-sparing agents, such as calcineurin inhibitors (e.g. ciclosporin or tacrolimus) and/or corticosteroids, sometimes along with antiproliferative agents (e.g. azathioprine, mycophenolate mofetil or rapamycin; Table 35.2), inhibitors of mechanistic target of rapamycin (mTOR; e.g. temsirolimus, everolimus, sirolimus or deforolimus), anti-T cytotoxic (anti-Tc; abatacept, belatacept) or anti-interleukin-2 (basiliximab, daclizumab) agents, or other biological therapies. Many new agents are being trialled, such as eculizumab and bortezomib for treatment of antibody-mediated rejection; these and the more commonly used immunosuppressive drugs and agents, along with their adverse effects, are discussed more fully in Chapter 19. Transplantation regimens used in children may affect the developing dentition.

Adverse effects may include the following:

A number of drugs can interfere with immunosuppressive agents (see Tables 35.4, 29.1 and 29.2).