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

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 of acute and chronic ABMR remains non-specific however.

#### **5.1. Acute antibody-mediated rejection**

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

Modern therapies can efficiently reverse acute renal dysfunction from ABMR, but they usually fail to deplete antibody-secreting plasma cells from the spleen and bone marrow of allograft recipients.[25] Hence, after a clinical episode of acute ABMR, DSAs remain in circulation and cause slowly progressive microvascular abnormalities without acute compromise of graft function, at least initially. This truncated form of antibody-mediated injury is called subclinical

In 1991, Feucht and co-workers discovered peritubular capillary deposition of C4d, an inactive product of the classic complement pathway [28] in the histology of cases of ABMR. This greatly improved the understanding and diagnosis of ABMR. It was called the "footprint" of antibody mediated tissue injury. It soon became a requisite to test for C4d in all transplant allograft biopsies. However, it has been recognised over time that C4d may only be the tip of the iceberg of the humoral process and that it was neither completely specific nor sufficiently sensitive for

C4d negative ABMR usually occurs more than 12 months after transplantation, but can occur acutely in highly sensitised patients with persistent DSAs (even after desensitisation).

There have been many theories put forth to explain the presence of microvascular inflamma‐ tion on biopsy and presence of DSAs in circulation, without any evidence of complement deposition. One is the technical issues related to type of fixative used and different methods of C4d detection. Another is that some DSAs are poor at fixing complement. Also, some believe the existence of a complement-independent pathway.[4] Furthermore, it is thought that as a result of treatment of high risk patients, the clinical and histological presentation of ABMR has

This phenomenon has been recognised for many decades. It is evidenced by monocytic and lymphocytic inflammation of the intima, myofibroblast proliferation and extracellular matrix deposition causing mild to severe intimal arteritis and compromise of the lumen. It is a major component of graft rejection but thought to be cell mediated. However, in 2003 Banff criteria,

Studies suggest that in DSA-positive patients there is significant acceleration of arteriosclero‐ sis.[11] Pathological examination demonstrated that while there is active ABMR, the intima is

lesions occur in ABMR.[31]

lesions have been classified to reflect probable ABMR. More and more, studies have

ABMR that have emerged are indolent ABMR and C4d –negative ABMR.

**4.1. Indolent ABMR**

448 Current Issues and Future Direction in Kidney Transplantation

or indolent ABMR. [26, 27]

**4.2. C4d-negative disease**

the diagnosis of ABMR[12, 29, 30].

**4.3. Acceleration of arteriosclerosis**

and v2

changed.[3]

the v3

shown that even v1

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 acute tubular necrosis or acute cellular rejection.

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 is sensitive enough to detect all cases of ABMR.

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.

**Figure 3.** Peritubular Capillaritis (dilatation of capillaries and margination of monocytes [white arrows])

Advances in Antibody Mediated Rejection http://dx.doi.org/10.5772/54855 451

**Figure 4.** Fibrinoid necrosis of small arteries (v3 lesion)

**Figure 1.** Acute tubular necrosis (ATN) in acute ABMR

**Figure 2.** Glomerulitis (infiltration of capillary loops by monocytes [white arrows])

**Figure 3.** Peritubular Capillaritis (dilatation of capillaries and margination of monocytes [white arrows])

**Figure 4.** Fibrinoid necrosis of small arteries (v3 lesion)

**Figure 1.** Acute tubular necrosis (ATN) in acute ABMR

450 Current Issues and Future Direction in Kidney Transplantation

**Figure 2.** Glomerulitis (infiltration of capillary loops by monocytes [white arrows])

The most recent Banff meeting update highlights two major phenotypes of ABMR. The first type appears early in the post-transplant period in a presensitized patient and is more likely to be C4d-positive. The second type develops late post-transplant, is due to de novo DSA development and is likely to be C4d-negative [36]. The second phenotype is an important factor in late graft loss[37]. It appears that Class II HLA molecules may be responsible and that much of the endothelial damage is mediated by NK cells and, to a lesser extent, monocytes and

Advances in Antibody Mediated Rejection http://dx.doi.org/10.5772/54855 453

The term "chronic ABMR" does not relate to a particular time post-transplantation, but rather to architectural remodelling which can affect all compartments of the biopsy. In addition,

**Figure 7.** Active chronic ABMR. Severe peritubular capillaritis is seen in the setting of interstitial fibrosis (ci) and tubu‐

The hallmarks of chronic ABMR are transplant glomerulopathy (TG) and multilayering of peritubular capillary basement membranes, with or without transplant arteriopathy (TA) and interstitial fibrosis and tubular atrophy, indicating that the microcirculation is the main target of humoral attack. Transplant glomerulopathy manifests as double contours in silver-stained sections and is well demonstrated by electron microscopy (figure 8). There is widening of the subendothelial space by flocculent material and eventual duplication of the glomerular

neutrophils (antibody-dependent cell-mediated cytotoxicity (ADCC) [38].

active ABMR may be superimposed on these changes. (Figure 7)

**5.2. Chronic antibody-mediated rejection**

**Microcirculation Injury**

lar atrophy (ct)

**Figure 5.** Diffuse C4d staining (immunoperoxidase method)

**Figure 6.** Diffuse C4d staining (immunofluorescence method)

The most recent Banff meeting update highlights two major phenotypes of ABMR. The first type appears early in the post-transplant period in a presensitized patient and is more likely to be C4d-positive. The second type develops late post-transplant, is due to de novo DSA development and is likely to be C4d-negative [36]. The second phenotype is an important factor in late graft loss[37]. It appears that Class II HLA molecules may be responsible and that much of the endothelial damage is mediated by NK cells and, to a lesser extent, monocytes and neutrophils (antibody-dependent cell-mediated cytotoxicity (ADCC) [38].
