**1. Introduction**

Kidney transplantation is considered the treatment of choice for patients with end-stage renal disease, and is associated with improved survival, better quality of life and reduced costs when compared with dialysis.[1, 2] However, the renal transplantation waiting list is forever growing, out of proportion to the number of donors.[2, 3] Therefore it is all the more crucial to develop strategies to extend the life and functionality of every allograft.

Rejection is no longer considered as a primarily T-cell-mediated process. We are fast realising that inadequate control of the humoral arm of a recipient's immune system is the pathogenic factor primarily responsible for allograft dysfunction and loss. The destructive power of anti-Human Leucocyte Antigen (HLA) alloantibodies and their association with antibodymediated rejection (ABMR) has been demonstrated and compelling evidence exists to show that donor-specific anti-HLA antibodies (DSAs) are largely responsible for the chronic deterioration of allografts, and may be a major contributor to the entity of chronic allograft nephropathy (CAN).

ABMR must now be considered to be a spectrum of diseases; which include indolent ABMR, C4d-negative ABMR, and transplant arteriopathy— in which DSAs have significant patho‐ logical effect. Also it has been shown that arteriosclerosis is accelerated in ABMR.[4-11]

A dynamic and progressive process of injury and repair that ultimately contributes to failure of the allograft is considered the hallmark of ABMR.[12]

It has been demonstrated that glomerular endothelial swelling, subendothelial widening, and early glomerular basement membrane duplication (precursor lesions) appear in the first weeks after transplantation in a substantial number of crossmatch-positive kidney transplant recipients.[13] Thus suggesting that the process of chronic antibody-mediated changes

(transplant glomerulopathy) may occur earlier than previously reported.[12, 13] In addition, DSAs can emerge at any time after transplantation and need not be present prior to trans‐ plantation.[14] Another important issue is that DSAs may differ in terms of their pathogenicity and so have varying prognosis. [14]

to occur in such situations[4]. However, recent data by Montgomery *et al.*[19] demonstrated a significant reduction in the risk of mortality among highly sensitized patients who underwent desensitization and transplantation compared with a well-controlled group of patients who remained on dialysis. These authors concluded that desensitization followed by living-donor transplantation offered significant survival benefit and that the survival advantage more than

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In addition to DSAs existing prior to transplant, it has been realised that they can emerge at any time after transplant, thus mediating allograft injury [14]. These *de novo* DSAs are different in their pathogenicity. They are active against class II HLA and are associated with a worse

DSAs can cause all types of ABMR, including chronic ABMR, otherwise known as transplant

The pathophysiology of ABMR is not fully understood, but is an area of rapidly expanding research. Several different patterns of allograft injury have been realised. These are initiated by DSAs which bind to HLA antigens or to other targets on the allograft endothelium.

As mentioned earlier, the pathogenicity of DSAs is influenced by the isotype of the heavy chain. Therefore, if DSAs are complement activating (IgG1 and IgG3), by binding IgG and activation of C1q the classic complement pathway is rapidly activated[21] resulting in rapid loss of graft. Alternatively, DSAs can bind to endothelial cell targets and stimulate cell proliferation (NK cells) or induce antibody-dependent cell- mediated cytotoxicity (ADCC) with interferon γ

Antibodies can also bind to HLA and other targets and incompletely activate the complement system (that is, no C5b-C9 membrane attack complex generation) without causing apparent injury. This process is referred to as accommodation.[22, 23] In addition, the long-term lack of ADCC may be related to IgG Fc polymorphisms that lead to the failure of activation of NK cells through FcγR (CD16)-dependent pathways[24] thus creating a greater degree of difficulty

Protocol biopsy studies have shown that substantial oscillations occur in a patient's humoral status during the first 12 months after kidney transplantation. These oscillations are charac‐ terized by fluctuations in DSAs, C4d deposition and scores for glomerulitis and/or capillaritis in a dynamic and multidirectional fashion.[12] Hence, the new concept that allograft injury is unlikely the result of a single episode of ABMR, but instead that it represents a dynamic process of injury and repair that begins early after transplantation and continues, unabated, at varying

The most florid form of ABMR, hyperacute rejection, has been almost completely eliminated, owing to greatly improved crossmatching techniques between recipients and prospective

doubled by 8 years.

**4. ABMR**

release.[4, 21]

in assessing pathogenicity of DSAs.

levels thereafter.[3, 12]

prognosis than DSAs against Class I HLA [14].

glomerulopathy.[4, 5, 7-10, 20]

Currently, treatment options for ABMR are aimed at antibody reduction and the inhibition of complement activation and injury. These include plasma exchange with low-dose IVIG, highdose IVIG and rituximab for antibody reduction, and high-dose IVIG for complement and C3 convertase inhibition and the absorption of complement activation fragments (such as C3a, C5a and C4b). Eculizumab (monoclonal anti-C5 antibody) and inhibitors of C1 are likely to show benefit in the prevention and treatment of ABMR.

Advances in B-cell-directed immunotherapeutics will have a considerable impact on DSA production, and consequently ABMR and allograft loss.

This chapter reviews the current understanding of antibody mediated rejection, and details its diagnosis, and treatments, both those established in current routine clinical practice and those on the horizon.
