**1. Introduction**

The first successful kidney transplant was performed between identical twins by Joseph E. Murray and his colleagues at the Peter Bent Brigham Hospital in 1954 [1]. Since then, the field of kidney transplantation has progressed immensely owing to greater understanding of the immune mechanisms underlying allograft rejection at a cellular and molecular level and development of increasingly potent immunosuppressive drug therapies [2]. Today, kidney transplantation is considered the treatment of choice for patients with end stage renal disease (ESRD) since it is associated with lower mortality and cardiovascular morbidity while offering

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**3. Clinical relevance of antibody mediated rejection**

AMR is estimated to occur in 3–10% of transplant recipients and it represents 20–30% of episodes of acute rejection [7]. Although less common than cell mediated rejection, AMR is generally recognized to have a worse prognosis and requires different forms of therapy [9]. In the 1960s anti-HLA antibodies were recognized as a cause for allograft rejection following reports of hyperacute antibody mediated rejection in patients with antibodies reactive to donor lymphocytes [10, 11]. Patel and Terasaki's landmark study documented immediate graft failure in 24 of 30 (80%) of the patients with circulating donor reactive antibodies identified by a positive cytotoxicity crossmatch [12]. This led to the universal practice of antibody screening by complement dependent cytotoxicity (CDC) crossmatch prior to renal transplantation and the avoidance of transplantation in patients with a positive crossmatch. Therefore, until the mid-1980s, acute cellular rejection, as opposed to antibody mediated rejection (AMR), was considered the major barrier to successful [13]. The advent of calcineurin inhibitors (CNIs) in the 1980s led to a significant decline in incidence of acute rejection and a consequent improvement in short term graft survival rates [14]. Today, cellular rejection seldom causes graft loss [15]. However, contemporary data suggests that these gains have not led to sustained improvement in long-term graft survival [16]. Reasons for the lack of improvement in long-term graft survival have been a topic of much debate and most late graft losses were attributed to either chronic allograft nephropathy (CAN) or death with a functioning graft [17]. Although, the multifactorial nature of late renal allograft loss makes therapeutic intervention challenging [18] prevention and treatment of AMR holds the key to optimizing long term graft survival. Exposure to non-self HLA by way of pregnancy, blood transfusion or transplantation may lead to the development of circulating anti-HLA antibodies. ESRD patients who are sensitized to HLA by prior exposure have a prolonged wait-time for transplantation and reduced transplant rates. Removal of pre-formed circulating donor specific antibodies (DSA) by various desensitization techniques allows transplantation of many of these biologically disadvantaged patients [19–21] However, such HLA incompatible kidney transplants recipients are at increased risk for developing AMR.A high percentage of episodes of AMR are difficult to treat and may cause immediate graft loss or delayed transplant glomerulopathy [22]. Therefore, AMR remains a

Diagnosis, Treatment, and Outcomes of Antibody-Mediated Rejection in Kidney Transplantation

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significant impediment to the success of transplantation in this subset of patients.

The Banff classification schema has been used internationally for scoring and classifying kidney transplant pathology findings since its first iteration was published in 1993. However, earlier versions dealt with AMR in an imprecise manner. The development of more sophisticated methods of detection of DSAs by means of solid-phase assays together with the sensitivity and specificity of C4d staining in peritubular capillaries in identifying AMR paved the way for rigorous morphological classification of AMR [23]. The cornerstones for the diagnosis for AMR are (1) Histologic evidence of acute tissue injury; (2) Evidence of current/recent antibody interaction with vascular endothelium; (3) Serologic evidence of DSAs. The updated 2015 Banff classification system recognizes acute active AMR and chronic active AMR and

**4. Diagnosis of antibody mediated rejection**

outlines detailed criteria for the diagnosis of each (**Table 1**) [24].

**Figure 1.** In AMR, DSAs bind to human leukocyte antigens on graft vascular endothelium. This is followed by activation of complement, membrane attack complex-mediated cellular injury and infiltration of mononuclear cells. Reproduced with permission from Montgomery et al. [4].

improved quality of life [3]. However, allograft rejection remains a major impediment to the longevity of renal allografts. Recognition of donor antigens as "non-self" by the host immune system elicits humoral and cell mediated immune responses that if left unchecked result in the destruction of the allograft (**Figure 1**).
