Transplantation surgery

Afferent arm

Antigen presentation: Donor major histocompatibility antigens (MHC) are recognised as foreign (allorecognition) by recipient T cells following presentation upon donor (direct) or recipient (indirect) antigen-presenting cells, such as dendritic cells and B cells ( Fig. 26.1 ).

T-cell receptor binding and costimulation: MHC antigen binding to T-cell receptors in the presence of costimulatory molecules can result in a number of possible outcomes, depending on the costimulatory stimulus, and these include T-cell activation, apoptosis (programmed cell death) or anergy (lack of response to antigen or antibody).

T-cell activation: Following their clonal expansion, T cells differentiate into helper (CD4 ⁺ ) and effector (CD8 ⁺ ) cells that secrete cytokines and kill target cells. Engagement of CD4 ⁺ T (helper) cells plays a central role in initiating and amplifying the rejection response.

B-cell activation: Traditionally seen as purely antibody-producing cells, it is clear that B cells contribute to the alloimmune response in a variety of additional ways: as antigen-presenting cells and through cytokine production. Complex interactions between CD4 ⁺ T cells and

B cells also lead to the production of donor-specific antibodies that play a crucial role in antibody-mediated rejection. If a patient has been previously exposed to foreign HLA molecules, for example, through pregnancy, blood transfusions or a previous transplant, they may have developed antibodies to those proteins, known as immunologic memory. This leads to a rapid antibody-mediated response and damages the transplanted organ.

Efferent arm

Donor organ damage can be mediated via cellular or antibody-mediated (humoral) mechanisms. The latter depends on B lymphocyte maturation and the production of complement-activating antibodies. The former, also known as delayed-type hypersensitivity (DTH), involves cytotoxic T cells, natural killer (NK) cells, macrophages and neutrophils.

Regulatory cells

It is becoming increasingly clear that the immune response is a dynamic balance of activating and regulatory cells, and the contribution of regulatory T and B cells is of particular interest. Regulatory T cells (Tregs) are best characterised as CD4+CD25+ and depend on the transcription factor foxp3. Tregs suppress some of the inflammatory cytokines, such as IL-2, and produce IL-10. Less is known about regulatory B cells, but they are of interest in our understanding of transplant tolerance or immune nonresponsiveness.

Acute cellular rejection

• Occurs in approximately 20% transplants, most commonly in the first 6 months

• Associated with immune cell infiltration, predominantly T cell-mediated, and can be treated with high-dose intravenous methylprednisolone

• Diagnosed on renal transplant biopsy and classified according to Banff 2017 diagnostic criteria ( Table 26.1 ).

  Table 26.1

  Banff 2017 diagnostic criteria for renal allograft biopsies

  Adapted from Haas M, Loupy A, LeFaucheur C, Roufosse C, Glotz D, et al. American Journal of Transplantation, 2018: 18:293–307.

  Category 1	Normal biopsy or nonspecific changes
  Category 2	Antibody-mediated changes Active antibody mediated rejection (ABMR) Chronic active ABMR
  Category 3	Borderline changes Suspicious for acute T-cell-mediated rejection
  Category 4	Acute T cell mediated rejection Chronic active T-cell-mediated rejection

Antibody-mediated rejection

• Caused by circulating antibodies that react to donor endothelium

• Diagnostic criteria for AMR are

  • i)

    histologic evidence of acute injury,

  • ii)

    evidence of antibody interaction in the kidney, e.g., complement fragment 4d (C4d) positivity and

  • iii)

    circulating antibody

• Treatment is more challenging and usually involves plasma exchange and intravenous immunoglobulin.

Chronic allograft damage

• Occurs after 6 months and often leads to a progressive decline in, and eventual loss of, organ function

• Multifactorial aetiology: immune-mediated injury, IRI, toxicity from immunosuppressive agents and viral infections

• Characterised histologically by cellular atrophy and fibrosis; there are currently no therapeutic strategies to combat it.

Corticosteroids

• Play an important role in induction and maintenance and are the first-line treatment for acute rejection

• Side effects of steroids are numerous and are responsible for many of the long-term complications of immunosuppressive therapy ( Table 26.2 )

  Table 26.2

  Side effects of corticosteroids

  Hypertension Diabetes mellitus Osteoporosis Peptic ulceration Cushingoid features Pancreatitis Poor wound healing Psychiatric disorders

• Several groups have explored reduction of the steroid load through various strategies:

  • a)

    Steroid withdrawal, undertaken some time after transplantation

  • b)

    Steroid avoidance, in which steroids are stopped a few days postoperatively

  • c)

    Steroid free

Whilst the benefits of reduced steroid use have been observed in these studies, steroid free and steroid withdrawal are associated with an increased incidence of biopsy-proven acute rejection at 12 months posttransplant.

Antiproliferative agents: mycophenolate mofetil (MMF)

• Prodrug for mycophenolic acid (MPA), which prevents lymphocyte activation by inhibiting DNA formation

• Has replaced azathioprine in many renal transplant patients, following the publication of several randomised trials that demonstrated reduced treatment failure at 6 months postkidney transplant

• Side effects include gastrointestinal disturbances, leucopenia, thrombocytopenia and anaemia.

Calcineurin inhibitors: tacrolimus

• Led to significantly improved 1-year outcome in liver and renal transplant patients compared with cyclosporin

  • 3C Study Collaborative Group. AM J Transplant 2018:18(6):1424–1434.

  • Adapted from Muduma G, Saunders R, Odeyemi I, Pollock R. Plos One 2016: 11(11) .

  EBM 26.3

  Immunosuppression

  • Tacrolimus offers improved mortality and hypertension rates compared with ciclosporin

  • Ciclosporin gives lower risk of new onset diabetes after transplantation versus tacrolimus

  • Sirolimus gives increased risk of rejection and infection with no improvement in transplant function compared with tacrolimus

• Is now the mainstay of many immunosuppressive regimens

• Side effects include nephrotoxicity, neurotoxicity, diabetes and alopecia ( EBM 26.3 ).

Antibody therapies

Antibody therapies may be used as induction therapy peritransplantation or for treatment of acute rejection.

Antibody therapies may be depleting or nondepleting:

• Depleting antibodies: Target cells are removed from the peripheral blood, including rabbit antithymocyte globulin (ATG) and alemtuzumab. They may be used as induction therapy or to treat steroid-resistant rejection.

• Nondepleting antibodies: In which the function of the target cells is affected, e.g., the interleukin-2 receptor antibody, basiliximab. This is used as induction therapy, reducing acute rejection rates, with few side effects.

New therapies

• Belatacept: Acts through T-cell costimulatory blockade and has been introduced in clinical trials with the aim of reducing requirement for calcineurin inhibitors

• Bortezomib: Acts as a proteasome inhibitor, inhibiting the production of antibody-producing plasma cells; it is used in antibody-incompatible transplants, to reduce the level of circulating donor-specific antibody and in cases of refractory antibody-mediated rejection

• Eculizumab: Understanding the key role of complement in mediating antibody damage has led to the development of the complement inhibitors such as the monoclonal antibody, eculizumab. It has been used to prevent antibody-mediated rejection and to reduce the risk of recurrent atypical haemolytic uraemic syndrome (aHUS) posttransplant.

Infection

The risk of infection is related to the dose of immunosuppression and is therefore greatest early after transplantation. Bacterial infections are most common during the first month. Viral infections are most common between 1 and 6 months and, of these, cytomegalovirus (CMV) is the most clinically relevant. The risk of CMV disease is reduced using antiviral agents such as valganciclovir prophylactically. Opportunistic infections with protozoa and fungi are also important, and most patients receive up to 6 months’ cotrimoxazole prophylaxis against Pneumocystis jirovecii.

Malignancy

The risk of developing skin cancer is particularly high, with squamous cell carcinoma being 20 times more common in transplant patients than in the normal population. Posttransplant lymphoproliferative disorders (PTLDs) are usually related to infection with Epstein–Barr virus and are associated with a high risk of developing B-cell lymphoma. Treatment of PTLD involves reduction in immunosuppression and, in some cases, chemotherapy.