**1. Introduction**

Antibody-mediated rejection (ABMR), also termed humoral rejection, is one of the most important causes of allograft dysfunction and loss accounting for up to 76% of death-censored graft failures beyond the first year of transplantation [1, 2]. According to current evidence, B cell and plasma cell activation results in the generation of donor-specific antibodies (DSAs), which bind to human leukocyte antigen (HLA) or non-HLA molecules expressed on endothelial cells within the renal allograft [3].

ABMR often represents a pathological spectrum that co-exists with T-cellmediated rejection [3]. Active (acute) ABMR is characterized by serological evidence of DSA, peritubular capillaritis, glomerulitis, cellular necrosis, thrombotic microangiopathy, and a relatively rapid decline in allograft function. The response to currently available therapies is often favorable. Chronic ABMR, on the other hand, is characterized by transplant glomerulopathy, a distinct pathophysiological process resulting from a repetitive pattern of thrombotic events and inflammatory changes that lead to endothelial cell injury and allograft matrix remodeling. It usually results in a slow and progressive decline in renal function, unlikely to be reversed by current therapeutic strategies [3, 4].

### **2. Pathogenesis**

In the 1960 Kissmeyer et al. [5] were the first to observe the deleterious impact of allo-antibodies in kidney grafts. Since then great advances have

occurred in solid organ transplantation. Nowadays, it is believed that immunologic reactions associated with ABMR can be triggered by circulating antibodies against donor HLA, non-HLA or ABO antigens, i.e. donor specific antibodies (DSAs) [6].

DSAs are most commonly directed against human leukocyte antigen (HLA)/ major-histocompatibility-complex (MHC) class I and II antigens [7]. HLA class I antigens are expressed on all nucleated cells, whereas HLA class II antigens are restricted to antigen-presenting cells (B lymphocytes, dendritic cells) and endothelial cells [8]. In addition to DSAs existing prior to transplant due to recipient sensitization (pregnancy, blood transfusions, and previous transplantation), it has been realized that they can emerge at any time after transplant, thus mediating allograft injury [9, 10]. These *de novo* DSAs are different in their pathogenicity. Those directed against class II HLA are associated with a worse prognosis than DSAs against class I HLA [10].

However, the antibodies can also be directed against other donor specific antigens such as MHC-class I-related chain A (MICA) antigens, MHC-class I-related chain B (MICB) antigens, platelet-specific antigens, molecules of the renin-angiotensin pathway, and polymorphisms involving chemokines and their receptors [11–13]. MICA antigens are expressed on endothelial cells, dendritic cells, fibroblasts, epithelial cells, and many tumors, but not on peripheral-blood lymphocytes [12].

The major mechanism involved in antibody-mediated kidney injury is activation of the classical complement pathway by the binding of DSA to HLA and subsequent binding of the C1 complex, which ultimately leads to formation of the membrane attack complex (C5b-C9) (**Figure 1**) [14, 15].

This leads to activation of polymorphonuclear inflammatory cells, NK cell and monocyte recruitment and inflammation, as well as activation of the coagulation cascade, which in turn leads to widespread microvascular injury evident as peritubular capillaritis, glomerulitis and microvascular thrombosis. B-cell responses against MHC antigens are T-cell dependent and require the involvement of antigen-presenting cells and costimulatory molecules such as CD40 ligand or soluble interleukins. These responses take 2–3 weeks to develop and lead to immunologic memory, allowing a more efficient antibody response upon repeat stimulation. Eventually transplant glomerulopathy develops (chronic phase) due to recurrent injury and repair with glomerular basement

#### **Figure 1.**

*Activation of classical complement pathway in ABMR in renal transplant recipients. Following binding of DSA to the vascular endothelium of kidney allograft, the C1 complex activates the serine esterases C1s and C1r, resulting in the cleavage of C4, deposition of C4d, and the assembly of the classical pathway C3 convertase. C3 convertase cleaves C3 into C3a, a potent pro-inflammatory mediator, and C3b, which propagates the complement cascade and leads to the formation of the pro-inflammatory mediator C5a and the membrane attack complex (C5b-C9). For more details, see Stegall et al. [15] ABMR-antibody-mediated rejection; DSAdonor-specific antibody; HLA-human leukocyte antigen.*

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**Figure 2.**

*artery [(D) HE, 200×].*

*Antibody Mediated Rejection in Kidney Transplant Recipients*

**3. Diagnostic criteria for antibody mediated rejection**

membrane remodeling, mesangial matrix expansion, capillary obliteration, foot process effacement [15]. Microcirculation remodeling at the level of peritubular capillaries progresses to interstitial fibrosis and tubular atrophy causing

By light microscopy, active antibody mediated rejection is characterized by 3 types of tissue injury: acute tubular injury, microcirculation inflammation with neutrophils and mononuclear cells in glomeruli and peritubular capillaries, and

Acute tubular injury includes loss of brush borders, thinning of tubular epithelial cells cytoplasm, shedding of tubular epithelium, and focal loss of nuclei (**Figure 3**). Focal necrosis of tubules can be found in minority of cases. In addition to oedema without significant interstitial infiltrate, proximal tubules express HLA-DR (**Figure 4**). Microcirculation inflammation with neutrophils and mononuclear cells in glomeruli and peritubular capillaries appears as glomerulitis and peritubular capillaritis. Glomerular capillaries are dilated and filled with swollen endothelial cells and inflammatory cells (**Figure 5**). In severe cases, glomerular capillary thrombosis can be detected (**Figure 6**). In glomerular injury due to ABMR usually predominates macrophages which express CD68 and neutrophils.

*Features of active antibody mediated rejection: Acute tubular injury [(A) hematoxylin-eosin stain (HE), 200×], microcirculation inflammation with neutrophils and mononuclear cells in glomeruli-glomerulitis [(B) HE, 400×] and peritubular capillaries-peritubular capillaritis [(C) HE, 200×], and fibrinoid necrosis of* 

*DOI: http://dx.doi.org/10.5772/intechopen.85886*

allograft failure.

**3.1 Histopathological features**

fibrinoid necrosis of arteries (**Figure 2**) [14].

membrane remodeling, mesangial matrix expansion, capillary obliteration, foot process effacement [15]. Microcirculation remodeling at the level of peritubular capillaries progresses to interstitial fibrosis and tubular atrophy causing allograft failure.
