Introduction

For many patients, the optimal treatment of their end-stage renal failure (ESRF) is kidney transplantation because it not only improves quality of life but may also confer survival benefits (EBM 25.1). Liver, heart and lung transplantation can be truly life-saving, as often no alternative treatments are available. The two main obstacles to transplantation are overcoming the recipient’s immune response and a shortage of donor organs.

Transplant immunology

The basis of transplant immunology is the host’s recog-nition of foreign tissue and its subsequent response to that. Our understanding of the molecular basis of this response has developed significantly over the last 50 years, which has allowed clinical transplantation to expand enormously. The process of transplant rejection, caused by infiltrating leucocytes, exhibits both specificity and memory and is prevented by lymphocyte depletion. The major histocompatibility complex (MHC) encodes the predominant transplant antigens responsible for acute rejection, and these are identical to serologically defined human leucocyte antigens (HLA).

The recipient’s immune response to the donor organ

Early events

Inflammation lies at the heart of the rejection process and is activated through early events around the time of transplantation. Brain-stem death and retrieval of organs, as well as cold ischaemic time (while the organ is stored on ice) and a period of warm ischaemia (while the vascular anastomoses are completed) stimulate an early inflammatory response to the transplanted organ. Reperfusion is associated with endothelial activation and the infiltration of inflammatory cells, particularly macrophages. The importance of this early ischaemia reperfusion injury (IRI) in shaping the patient’s subsequent course is illustrated by the superior outcome observed following living donor transplantation, despite more significant major histocompatibility (MHC) mismatching, and the adverse impact of a more prolonged cold ischaemic time on graft outcome. Indeed, the severity of this inflammatory injury modulates the subsequent alloimmune response, generating a ‘danger signal’ which primes the immune response to the transplanted organ. Thus, IRI impacts upon long-term outcome: it leads to a delay in primary graft function, increases acute rejection rates and reduces long-term graft survival (EBM 25.2). The crucial role of IRI in mediating transplant-associated injury has become more apparent as acute rejection rates fall with the introduction of new and highly effective immunosuppressive agents, and has led to an increasing interest in how IRI may be reduced through preconditioning strategies.

25.2 Impact of delayed graft function on long term outcome

‘Delayed graft function, defined as the requirement for dialysis during the first week following transplantation is associated with:

41% increased risk of graft loss at 3 years

Higher serum creatinine at 3.5 years

38% relative increased risk of acute rejection,

Compared with patients that have primary function’

Yarlagadda SG, Coca SG, Formica RN Jr, Poggio ED, Parikh CR. Association between delayed graft function and allograft and patient survival: a systematic review and meta-analysis. Nephrol Dial Transplant. 2009 Mar;24(3):1039-47. Epub 2008 Dec 22.

The afferent arm of the immune response

The immune response to the transplanted organ can be divided into afferent and efferent arms: the afferent arm includes presentation of donor antigen to recipient T cells, T cell receptor (TCR) binding and costimulation, which leads to T cell activation. The efferent arm describes the sequence of events that occurs as a result of T cell activation.

Antigen presentation

Donor MHC antigens are recognized as foreign (allo- recognition) by recipient T cells following presentation upon donor (direct) or recipient (indirect) antigen-presenting cells (APCs) (Fig. 25.1).

Fig. 25.1 Antigen presentation.

A Direct. B Indirect. (APC = antigen-presenting cell; MHC = major histocompatibility complex; TCR = T-cell receptor)

T-cell receptor binding and costimulation

MHC antigen-binding to the T-cell receptor (TCR) in the presence of certain co-stimulatory molecules leads the T cells to undergo clonal expansion. Engagement of the TCR can result in a number of possible outcomes, depending on the costimulatory stimulus, and leads to T-cell proliferation, apoptosis or anergy. Costimulatory blockade is an interesting therapeutic strategy which has recently been introduced into clinical practice, with some benefit.

T-cell activation

Antigen binding and costimulation leads to the activation and clonal expansion of T cells. T cells differentiate into helper (CD4-positive) and effector (CD8-positive) cells that are able to secrete cytokines and kill target cells. Engagement of the CD4-positive T (helper) cells play a central role in initiating and amplifying the rejection response.

The efferent arm of the immune response

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

Immunosuppression

The challenge is to minimize the risk of graft rejection with as few side effects as possible. Various strategies are adopted: induction therapy, maintenance immunosuppression and treatment of rejection. The mechanisms of action of the common immunosuppressive drugs are outlined on Figure 25.2.

Fig. 25.2 Mechanisms of action of common immunosuppressive agents.

Organ donation

The shortage of organs for transplantation remains a major challenge to the transplant community, with demand consistently outstripping supply over many years (Fig. 25.3). Such a shortage has led to significant changes in practice over the last decade, with an increasing number of patients undergoing transplants from living donors, and from marginal or extended criteria deceased donors. These will be discussed in this section.

Fig. 25.3 Number of cadaveric donors and transplants in the UK, 1 April 1995 to 31 March 2009, and patients on the waiting lists at 31 March each year (ODT statistics).

Donor management

Specific criteria must be met in order to make the diagnosis of brain-stem death (Table 25.4). Events leading up to brain death may impact upon the quality of the retrieved organs. Initially, at the point of brainstem death, compression associated with coning results in hypertension and bradycardia, known as the Cushing reflex. An autonomic storm ensues, characterized by the massive release of catecholamines, with resultant hypertension and hypoperfusion. The effect on cardiac function is the deterioration of ventricular systolic function, the liver and kidneys are affected by hypoperfusion, and it is likely that these changes contribute to non-specific endothelial cell damage, which increases the immunogenicity of the organs.

Table 25.4 Criteria for diagnosis of brain-stem death