**4. ABMR**

(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

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

Advances in B-cell-directed immunotherapeutics will have a considerable impact on DSA

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

Over the past two decades, our thinking has changed from considering rejection as a primarily T-cell-mediated process (one that is now increasingly better managed in the era of more potent calcineurin inhibitors and broader use of T-cell depleting therapies), to the realization that insufficient control of the humoral arm of a recipient's immune system by current immuno‐ suppressive regimens is now the pathogenic factor primarily responsible for allograft dys‐ function and loss.[13, 15, 16] This has changed our perception about allograft losses which were deemed to be caused by calcineurin inhibitor (CNI) toxicity and chronic allograft

Furthermore, the growing incidence of transplantation across HLA and ABO barriers by using desensitisation programs, but in the face of known DSAs, has led to increased incidence and a wider variety of ABMR. We are now exposed to a greater spectrum of antibody-mediated

Great advances have occurred in solid organ transplantation since the pioneering observation of Kissmeyer et al.[17] in the 1960s, of the deleterious impact of allo-antibodies in kidney grafts. About three decades later, the team of Edmonton described rejection episodes following kidney transplantation related to the presence of anti-HLA donor specific antibodies (DSA) [18]. The presence of DSAs and positive crossmatches with donors has long been considered a contraindication to proceeding with transplantation as ABMR and graft loss is highly likely

and so have varying prognosis. [14]

446 Current Issues and Future Direction in Kidney Transplantation

on the horizon.

**2. Rejection**

nephropathy (CAN).

**3. Donor Specific Antibodies (DSAs)**

graft injury.

show benefit in the prevention and treatment of ABMR.

production, and consequently ABMR and allograft loss.

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 release.[4, 21]

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 in assessing pathogenicity of DSAs.

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 levels thereafter.[3, 12]

The most florid form of ABMR, hyperacute rejection, has been almost completely eliminated, owing to greatly improved crossmatching techniques between recipients and prospective donors, particularly technologies such as flow-cytometry. These tests are much more sensitive for detecting a problem due to potential DSAs than older methods such as cell-dependent cytotocity (CDC). With the waning of hyperacute rejection, the different manifestations of ABMR that have emerged are indolent ABMR and C4d –negative ABMR.

hypercellular, laying down new collagen over older (usually originating from donor). Once ABMR is brought under control, the myofibroblasts stop proliferating, and the intima is no longer hypercellular. What is left behind is a lesion no different from simple arteriosclerosis

Advances in Antibody Mediated Rejection http://dx.doi.org/10.5772/54855 449

Chronic Antibody Mediated Rejection First described in 2001[33], the natural history of chronic humoral rejection is now well known.[12, 29, 34] The presence of DSAs activates the classical complement pathway causing peritubular multilamination and transplant glomer‐ ulopathy. These gradually become irreversible and cause permanent graft dysfunction. The main challenges are when to initiate treatment and how to treat it, as it may be too late to

Antibody-mediated rejection (ABMR) was described in the early 1990s but was not incorpo‐ rated into the Banff classification until 2001. Now, due to an expanding spectrum of clinical disease, two phenotypes of acute antibody-mediated rejection have been postulated and the chronic form of ABMR is recognized as a leading cause of late allograft failure. The histology

Three patterns of tissue injury reflect acute antibody-mediated damage. These are acute tubular injury (Figure 1), inflammation of glomerular and/or peritubular capillaries (so-called microcirculation inflammation) (Figure 2 and 3), and fibrinoid necrosis of arteries (v3 lesion) (Figure 4). Microcirculation inflammation may include a TMA-like pattern as well. It is immediately obvious that all three types are not specific for ABMR and may be encountered in a variety of clinical settings in the transplanted kidney. For example, the acute tubular injury pattern is similar to that produced by ischaemia and capillaritis can be seen in the setting of

For these reasons, it was recommended that histology be correlated with C4d immunomicro‐ scopy and donor-specific antibodies (DSA) status. The former is an inactive fragment, split from its parent molecule C4b during activation of the classical complement pathway, but due to covalent binding with the endothelium, able to persist at sites of complement activation. This covalent binding can be demonstrated with immunoperoxidase or immunofluorescent (Figure 5 and 6) techniques and serves as a marker of complement activation. Neither method

A positive C4d result on renal biopsy shows linear, circumferential endothelial reaction in peri‐ tubular capillaries by either method, although the immunoperoxidase signal may be less intense by one grade. Interrupted, granular deposition is considered non-specific. Diffuse and focal line‐ ar reaction in peritubular capillaries appears to correlate with glomerulitis and presensitization [36], however an important caveat is the ABO-incompatible renal allograft. In this situation, dif‐

fuse linear C4d may be seen in the absence of tissue injury and graft dysfunction.

of aging. This is termed "transplant arteriopathy".[11, 32]

**5. Pathology of antibody-mediated rejection**

of acute and chronic ABMR remains non-specific however.

slow or halt the progress of this injury.[34, 35]

**5.1. Acute antibody-mediated rejection**

acute tubular necrosis or acute cellular rejection.

is sensitive enough to detect all cases of ABMR.
