**5.3 Rituximab and proteasome inhibitors**

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 pneumococcus sepsis [58].

In renal transplantation rituximab is used for desensitization of highly sensitized patients or awaiting ABO-incompatible renal transplantation [59].

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 [59–62].

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.

## **5.4 Complement inhibition**

#### *5.4.1 C5 inhibitors*

Activation of the complement cascade in acute ABMR rejection has been identified as a major pathophysiological mechanism leading to allograft damage and dysfunction [65]. As a consequence, it has been proposed that specific inhibition of the recipient's complement system of limited duration may be useful to prevent acute ABMR.

The anti-C5 monoclonal antibody eculizumab, which inhibits terminal complement activation, was reported to decrease the incidence of early antibody-mediated rejection in HLA-sensitized renal-transplant recipients [66], although it failed to prevent chronic antibody-mediated rejection in recipients with persistently high levels of donor-specific anti-HLA antibodies [67]. It was also shown that preemptively usage of eculizumab following positive B-cell flow cytometric crossmatch transplant resulted in a reduced incidence of early ABMR from 41.0% in historical controls to 7.7% in eculizumab-treated patients [68].

#### *5.4.2 C1 inhibitors*

Binding of anti-HLA DSAs to complement fraction C1q, the first component in the activation of the complement cascade, has been associated with poor graft outcomes and severe phenotypes of ABMR [69]. These findings have provided the rationale for the use of proximal complement inhibition using C1 inhibitors (C1 INHs) in the treatment of ABMR. C1-INH is a serine protease inhibitor that inactivates both C1r and C1s and has multiple effects. Following antibody/immune complex activation of C1qrs, C1-INH dissociates C1r and C1s from the activated C1 macromolecule. This prevents proteolytic activation of C4 and C2 that form C3 convertase, which is important in the context of C4d deposition in AMR [70]. The use of a plasma-derived C1 INH in the treatment of active ABMR was evaluated in trial of 18 kidney transplant recipients with biopsy-proven, active ABMR [71], who were randomly assigned to receive C1 INH or placebo as adjunct therapy to standard-of-care treatment with PP, IVIG, and rituximab. Although there was no significant difference between the groups in posttreatment renal histopathology or graft survival on day 20, a trend toward sustained improvement in graft function at day 90 was observed in the C1 INH group.

Similar findings were reported in six kidney transplant recipients with active ABMR that were unresponsive to treatment with PP, IVIG, and rituximab [72]. All patients received the C1 INH Berinert (20 units/kg on days 1, 2, and 3 and then twice weekly) and high-dose IVIG (2 g/kg once per month) for 6 months. At 6 months, all patients showed an improvement in eGFR compared with baseline at the time of inclusion in the study. Renal allograft biopsies at 6 months revealed no significant change in histologic features; however, C4d deposition was observed in only one of six patients compared with five of six patients at baseline. In addition, of the six patients who were positive for a C1q-binding circulating DSA at the start of the study, only one had a positive DSA at 6 months.

#### **5.5 IL-6 inhibition**

The potential of proinflammatory cytokine blockade in kidney-transplant recipients with chronic ABMR has recently been highlighted [73]. Tocilizumab is a monoclonal antibody directed against the interleukin IL-6 receptor that has

**85**

*Antibody Mediated Rejection in Kidney Transplant Recipients*

evaluate IdeS treatment as a therapeutic strategy for ABMR.

ABMR, resistant to standard treatment [78–82].

Authors declare no conflicts of interest.

and preserving allograft function [81].

been used for the treatment of rheumatic diseases, such as rheumatoid arthritis and systemic juvenile idiopathic arthritis. Recently, tocilizumab was also evaluated as rescue therapy in 36 kidney transplant patients with chronic ABMR who failed standard-of-care treatment with IVIG and rituximab, with or without plasma exchange [74]. Tocilizumab was administered as 8 mg/kg monthly for 6 to 25 months. Significant reductions in DSAs and stabilization of renal allograft function were observed at 2 years. No significant adverse events or severe adverse events

IgG-degrading enzyme of *Streptococcus pyogenes* (IdeS) cleaves at a very specific amino acid sequence in the hinge region of human IgG and essentially neutralizes all of the IgG in the body within 4 hours of administration. There is a period of about 7 days during which both soluble IgG and the B cell receptor are not detectable, after which it begins to rebound and can reconstitute fully by day 14 [75]. In clinical trials ideS was used in attempting to evaluate the efficacy to desensitize transplant patients with a positive crossmatch, where it showed efficacy in reduction of anti-HLA antibodies before kidney transplantation in patients who were HLA-incompatible with their donors [76, 77]. Further studies are necessary to

A desensitization protocol may be required to avoid ABMR in patients that are highly sensitized, have positive crossmatch or ABO incompatibility, however current protocols are not always effective to prevent ABMR and in some cases fail to convert subjects to a negative crossmatch before transplantation. Studies have shown that splenectomy can be successfully performed alone or in association with other treatments like bortezomib, rituximab or eculizumab to overcome severe

In an effort to spare recipients the morbidity of a splenectomy, splenic irradiation in addition to other therapy may provide an effective intervention for rescuing

Antibody-mediated rejection is an important cause of acute and chronic graft failure. Diagnosis of acute and chronic ABMR is based on typical histological hallmarks, positive C4d in peritubular capillaries and presence of donor-specific antibodies (DSA). Among standard of care treatment based on PP and IVIG, new treatment options have become available: B cell depletion (rituximab), plasma cell depletion (bortezomib), complement activation inhibition (c1 and c5 inhibitors), recently also IL-6 inhibitors and ideS. However, the high cost of novel medications and a lack of prospective studies evaluating their efficacy and safety limit the routine use of these agents in the treatment of ABMR in kidney transplant recipients.

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

were reported.

**5.7 Splenectomy**

**6. Conclusions**

**Conflict of interest**

**5.6 IdeS**

*Antibody Mediated Rejection in Kidney Transplant Recipients DOI: http://dx.doi.org/10.5772/intechopen.85886*

been used for the treatment of rheumatic diseases, such as rheumatoid arthritis and systemic juvenile idiopathic arthritis. Recently, tocilizumab was also evaluated as rescue therapy in 36 kidney transplant patients with chronic ABMR who failed standard-of-care treatment with IVIG and rituximab, with or without plasma exchange [74]. Tocilizumab was administered as 8 mg/kg monthly for 6 to 25 months. Significant reductions in DSAs and stabilization of renal allograft function were observed at 2 years. No significant adverse events or severe adverse events were reported.

#### **5.6 IdeS**

*Perioperative Care for Organ Transplant Recipient*

controls to 7.7% in eculizumab-treated patients [68].

day 90 was observed in the C1 INH group.

of the study, only one had a positive DSA at 6 months.

Activation of the complement cascade in acute ABMR rejection has been identi-

The anti-C5 monoclonal antibody eculizumab, which inhibits terminal complement activation, was reported to decrease the incidence of early antibody-mediated rejection in HLA-sensitized renal-transplant recipients [66], although it failed to prevent chronic antibody-mediated rejection in recipients with persistently high levels of donor-specific anti-HLA antibodies [67]. It was also shown that preemptively usage of eculizumab following positive B-cell flow cytometric crossmatch transplant resulted in a reduced incidence of early ABMR from 41.0% in historical

Binding of anti-HLA DSAs to complement fraction C1q, the first component in the activation of the complement cascade, has been associated with poor graft outcomes and severe phenotypes of ABMR [69]. These findings have provided the rationale for the use of proximal complement inhibition using C1 inhibitors (C1 INHs) in the treatment of ABMR. C1-INH is a serine protease inhibitor that inactivates both C1r and C1s and has multiple effects. Following antibody/immune complex activation of C1qrs, C1-INH dissociates C1r and C1s from the activated C1 macromolecule. This prevents proteolytic activation of C4 and C2 that form C3 convertase, which is important in the context of C4d deposition in AMR [70]. The use of a plasma-derived C1 INH in the treatment of active ABMR was evaluated in trial of 18 kidney transplant recipients with biopsy-proven, active ABMR [71], who were randomly assigned to receive C1 INH or placebo as adjunct therapy to standard-of-care treatment with PP, IVIG, and rituximab. Although there was no significant difference between the groups in posttreatment renal histopathology or graft survival on day 20, a trend toward sustained improvement in graft function at

Similar findings were reported in six kidney transplant recipients with active ABMR that were unresponsive to treatment with PP, IVIG, and rituximab [72]. All patients received the C1 INH Berinert (20 units/kg on days 1, 2, and 3 and then twice weekly) and high-dose IVIG (2 g/kg once per month) for 6 months. At 6 months, all patients showed an improvement in eGFR compared with baseline at the time of inclusion in the study. Renal allograft biopsies at 6 months revealed no significant change in histologic features; however, C4d deposition was observed in only one of six patients compared with five of six patients at baseline. In addition, of the six patients who were positive for a C1q-binding circulating DSA at the start

The potential of proinflammatory cytokine blockade in kidney-transplant recipients with chronic ABMR has recently been highlighted [73]. Tocilizumab is a monoclonal antibody directed against the interleukin IL-6 receptor that has

fied as a major pathophysiological mechanism leading to allograft damage and dysfunction [65]. As a consequence, it has been proposed that specific inhibition of the recipient's complement system of limited duration may be useful to prevent

**5.4 Complement inhibition**

*5.4.1 C5 inhibitors*

acute ABMR.

*5.4.2 C1 inhibitors*

**84**

**5.5 IL-6 inhibition**

IgG-degrading enzyme of *Streptococcus pyogenes* (IdeS) cleaves at a very specific amino acid sequence in the hinge region of human IgG and essentially neutralizes all of the IgG in the body within 4 hours of administration. There is a period of about 7 days during which both soluble IgG and the B cell receptor are not detectable, after which it begins to rebound and can reconstitute fully by day 14 [75]. In clinical trials ideS was used in attempting to evaluate the efficacy to desensitize transplant patients with a positive crossmatch, where it showed efficacy in reduction of anti-HLA antibodies before kidney transplantation in patients who were HLA-incompatible with their donors [76, 77]. Further studies are necessary to evaluate IdeS treatment as a therapeutic strategy for ABMR.

#### **5.7 Splenectomy**

A desensitization protocol may be required to avoid ABMR in patients that are highly sensitized, have positive crossmatch or ABO incompatibility, however current protocols are not always effective to prevent ABMR and in some cases fail to convert subjects to a negative crossmatch before transplantation. Studies have shown that splenectomy can be successfully performed alone or in association with other treatments like bortezomib, rituximab or eculizumab to overcome severe ABMR, resistant to standard treatment [78–82].

In an effort to spare recipients the morbidity of a splenectomy, splenic irradiation in addition to other therapy may provide an effective intervention for rescuing and preserving allograft function [81].
