**5. Treatment**

Treatment for ABMR is not standardized, and there is still no evidence-based treatment guidelines. A recent therapy of ABMR in renal allografts is systematically reviewed by Wan et al. [2]. In addition to plasma exchange and intravenous immunoglobulin, which still present a backbone of treatment, a number of other therapies have been tried in small studies without consistent benefit, including anti-CD20, proteasome inhibitors, complement inhibitors, anti-interleukin-6 receptor blockers, and immunoglobulin G-degrading enzyme of *Streptococcus pyogenes* (IdeS).

#### **5.1 IVIG**

Intravenous immunoglobulin (IVIG) is used for treatment of ABMR, and it is used as an element of desensitizing protocols for ABO- and HLA-incompatible renal transplantation [40].

IVIG is prepared by human plasma from approximately 50,000–100,000 of healthy donors, composed of 90% intact IgG, a few dimers, Fabs (fragment antigen-binding) and traces of IgM and IgA [41].

There are many postulated immunomodulatory mechanisms of IVIG. Investigations in the early 1990s suggested the therapeutic potential of IVIG was due primarily to anti-idiotypic interactions with HLA antibodies [42]. Apart from its effects on B cells and phagocytes via Fc-gamma receptors, IVIG also functions as a scavenger of activated complement [43, 44].

Two general treatment protocols have been developed utilizing IVIG. The first is the use of high dose IVIG (2 g/kg) alone and the second is to combine lower dose IVIG with other modalities, usually plasmapheresis [45]. After the first successful report of Jordan et al. in 1998 [46] who treated acute ABMR in kidney and heart allografts by high-dose IVIG and methylprednisolone, there were more studies with usage of IVIG alone or in combination with plasmapheresis to show effectiveness in treatment of ABMR [47, 48].

**83**

[59–62].

*Antibody Mediated Rejection in Kidney Transplant Recipients*

therapeutic apheresis, decreasing infection risk [49].

Additional benefit of IVIG is its ability to replenish gamma globulin lost during

Both immunoabsorption (IA) and plasmapheresis (PP) are known to lower HLA-specific antibody levels in a variety of clinical settings [49]. Despite the substantial reductions in the titer of donor-specific anti-HLA antibodies achieved by IA and PP, the graft survival in these patients is significantly reduced, due to rebound

PP is the most frequent modality applied and generally involves 1.0–1.5 volume exchange, using albumin as replacement. It is usually performed daily or every other day for an average of six sessions (up to 14 days). The initial treatment is typically a one-and-one-half-volume exchange with albumin, and subsequent treatments are a one-volume exchange with albumin. To avoid fresh frozen plasma administration, most clinicians prefer an every-other-day PP schedule as albumin alone can often be administered for replacement with interval recovery of the prothrombin time, partial thromboplastin time, and fibrinogen to acceptable levels. This avoids the risk of antigen sensitization. IA is a more selective modality that uses adsorbent membranes for antibody elimina-

Few studies have been published where PP modalities are the sole or primary form of antibody reducing therapy [51–54]. However, PP alone has limited success in the treatment of ABMR, and this finding has led to the addition of therapies to prevent immunoglobulin resynthesis and B-cell proliferation. Therefore, PP is often used in combination with other antibody blocking (IVIG), suppression (rituximab, mycophenolate, calcineurin inhibitors), or depleting (bortezomib)

Rituximab is a chimeric monoclonal antibody directed against CD20, which is found on immature and mature B cells but not on plasma cells. Following treatment with rituximab, B cells undergo apoptosis and lysis [55]. Most adverse events are first infusion effects of generally mild severity. Additionally, an increased incidence of infections has been described including cases of progressive multifocal leukoencephalopathy [56], late onset Pneumocystis pneumonia [57] and fatal pneumococ-

In renal transplantation rituximab is used for desensitization of highly sensi-

The potential role of the anti-CD20 monoclonal antibody rituximab and the proteasome inhibitor bortezomib in decreasing the production of donor-specific anti-HLA antibodies and improving allograft survival in patients with antibodymediated rejection was recently evaluated in two randomized, controlled trials RITUX ERAH [63] and BORTEJECT [64], but neither trial showed clinical benefits.

In case of ABMR, rituximab is used for the treatment of ABMR as a solo agent adjuncted to standard of care therapy [60, 61] or in some instances combined with bortezomib, a proteasome inhibitor causing apoptosis of mature plasma cells [62]. Treatment of ABMR with rituximab or bortezomib or combination in addition to standard therapy was in most instances partially effective on the short term, whereas treatment did not result in sufficient long-term graft survival

tized patients or awaiting ABO-incompatible renal transplantation [59].

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

synthesis of de novo alloantibodies.

**5.3 Rituximab and proteasome inhibitors**

**5.2 Plasmapheresis**

tion [49, 50].

modalities [2].

cus sepsis [58].

Additional benefit of IVIG is its ability to replenish gamma globulin lost during therapeutic apheresis, decreasing infection risk [49].
