**6.4. Eculizumab**

**6. Treatment**

**6.1. IVIg**

unclear.[42]

**6.3. Rituximab**

emerged as adjunctive or experimental therapies.

456 Current Issues and Future Direction in Kidney Transplantation

ment activation fragments (e.g. C3a,C5a and C4b).[45]

antigen, the dose of IVIg and use of other agents.[42]

**6.2. Plasma exchange/plasmapheresis**

There has been significant development of newer and more specific therapies for ABMR. These are aimed at depleting B cells, antibodies and inhibiting complement, owing to the unique role of antibody and effector molecules in the process of ABMR. The therapeutic options include intensification of maintenance immunosuppression (e.g. tacrolimus and mycophenolate), plasmapheresis/plasma exchange, intravenous immunoglobulin (IVIg), corticosteroids and antilymphocyte antibodies. Rituximab, splenectomy, bortezomib, and eculizumab have also

The mechanism of action and the optimal dose of IVIg that should be administered in ABMR are poorly understood.[42], but it is thought to have an immunomodulatory effect. The proposed beneficial properties include compliment inhibition, suppression of immunoglobu‐ lin synthesis.[43, 44] High dose IVIg inhibits C3 convertase and the ability to absorb comple‐

There have been retrospective studies reporting improved one year graft survival in cases of steroid and antithymocyte resistant ABMR treated with protocols incorporating IVIg and plasmapheresis/ plasma exchange.[46-49] The need to combine plasma exchange is however,

Plasma exchange removes antibodies from the circulation. In the case of ABMR it is thought to be efficacious through the removal of DSAs. However, it does not suppress further pro‐ duction. In fact, it may stimulate rebound immunoglobulin production if used on its own. It is hence necessary to use it in conjunction with strategies which target antibody production (for example, the anti-CD20 monoclonal antibody rituximab). ABMR treatment protocols may utilise plasma exchange depending upon the antibody titre, the affinity of the antibody for the

This is a humanised mouse monoclonal antibody that targets CD20, which is expressed on the majority of B cells. However, most plasma cells lack CD20 and are unaffected by Rituximab. Hence, its role will be as an adjunctive treatment. A recent single centre study compared outcomes in 24 cases of ABMR treated with either high dose IVIg (2g/kg for four doses) versus plasmapheresis plus IVIg (100mg/kg) for four treatments followed by IVIg (2g/kg for four doses) and two doses of rituximab (375mg/m2). Improved 3-year survival (92% vs. 50%) and significantly reduced DSA at 3 months was observed in the plasmapheresis/IVIg/rituximab group.[6] It has also been seen to be effective when used as part of desensitization protocol in ABO- incompatible (ABOI) transplants, although there is concern over the cost of increased infections in recipients of such transplants. One study reported \patients who received B-cell Drugs that inhibit compliment and C1 are likely to show benefit in the prevention and treatment of ABMR and currently they are many human trials being conducted to evaluate their effect.[3, 51]

Eculizumab is an antibody against complement protein C5, and hence, inhibits the formation of the membrane attack complex (MAC). It is approved for use in paroxysmal nocturnal hemoglobinuria (PNH) and has had promising results in treatment and ongoing management of atypical haemolytic uraemic syndrome, for which it has also recently been approved for use. It is, however, and extremely expensive therapy. A single case reported the use of eculizumab in combination with plasmapheresis/IVIg to rescue a renal allograft undergoing severe ABMR, and showed significant reduction in C5b-C9 (MAC) complex deposition in the kidney.[52]
