**6. Treatments for antibody mediated rejection**

The success of desensitization techniques, which enabled transplantation in the setting of pre-existing DSA, represented a breakthrough in the ability to offer transplantation to highly-sensitized patients, who previously had little hope of receiving a transplant [32–34]. But early success was tempered by observations of antibody rebound, early AMR, and suboptimal long-term graft survival [35, 36]. Thus the ability to successfully perform incompatible transplants and optimize long-term outcomes is contingent upon the ability to successfully treat AMR. The first reported efforts at allograft rescue in the setting AMR employed similar techniques as were used for desensitization, namely, techniques that remove or reduce circulating antibody [37]. While removal of antibody remains the cornerstone of AMR therapy, improved understanding of the pathophysiological mechanisms of antibody production and antibody mediated injury have yielded several adjunctive treatment options which are now in various stages of application or new development. For treatment of AMR, no standard protocols exist. Published reports are generally small patient series, and reported techniques vary based on center-specific experience and expertise, as well as center-specific access to emerging therapies [38–40]. Thus, randomizedcontrolled trial data do not exist for most of these treatments. Meta-analyses are limited by patient heterogeneity, treatment regimen heterogeneity and sample size [39, 41]. Below are brief descriptions of currently existing treatment modalities, though it is important to understand that these are rarely, if ever, used as monotherapies. Most AMR treatment strategies employ a technique for antibody removal in combination with adjunctive agents to minimize antibody production and/or act at the level of the graft to minimize antibodymediated injury.

**6.2. Immunoadsorption**

**6.4. Splenectomy**

graft failures in the control group [54].

**6.3. Intravenous immune globulin (IVIG)**

beneficial in select patient situations [72].

**6.5. B-cell and plasma cell targeted medical therapies**

improved outcomes with the addition of rituximab [82].

Immunoadsorption (IA) is a therapy not available worldwide, but where applied has been used successfully in both desensitization and treatment of AMR. IA has the benefit of specifically removing circulating IgG, while sparing desired plasma protein components such as clotting factors [50]. IA can rapidly and efficiently deplete IgG after a small number of treatments [51–53]. A single randomized controlled trial reporting IA plus pulse steroid compared to pulse steroid alone as treatment for AMR was stopped early after an excessive number of

Diagnosis, Treatment, and Outcomes of Antibody-Mediated Rejection in Kidney Transplantation

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The precise mechanisms of IVIG action both in desensitization and in treatment of AMR remain unclear, but there is evidence to support that it is multimodal [55, 56]. IVIG has been shown to have inhibitory effects on B-cells [57–59], antigen presenting cells [60], and on complement [61, 62]. IVIG in the treatment of AMR has been reported as high-dose therapy (1–2 gm/kg) used without plasma exchange treatments [63–65], and more commonly, as low-

Removal of the spleen, the largest lymphoid organ in the body, is postulated to deplete the plasma cell reservoir, and thereby yield a rapid decrease in circulating HLA antibody in patients with severe acute rejection [67, 68]. Due to its associated morbidity, splenectomy is generally reserved as a rescue therapy [67, 69–71] when all other less invasive interventions are failing and a graft is at risk for imminent loss. Potentially less morbid alternatives to operative splenectomy, including angioembolization or splenic irradiation, may prove to be

Rituximab (Rituxan®, Genentech) is a monoclonal antibody directed against the B-cell CD20 antigen [73]. This recombinant antibody is constructed as a chimeric protein with human IgG1 constant regions linked to murine anti-human CD20 variable regions [74]. Binding of rituximab to CD20 leads to antibody-dependent complement-mediated cytotoxicity and apoptosis of the bound cell. Rituximab thereby depletes the memory B-cell population and this is hypothesized to, in turn, reduce the plasma cell population and decrease HLA-antibody production [75–77]. Rituximab has been used as an adjunctive therapy in combination with various treatment modalities including: IVIG [78], TPE plus steroid pulse [79, 80], and TPE plus IVIG [66, 81]. While rituximab was perhaps the earliest used adjunctive agent in the treatment of AMR, to date only a single randomized controlled trial of its use has been performed, in which it was compared to placebo in addition to standard therapy (TPE with low dose IVIG). No difference was observed in this underpowered study though there was a trend toward

dose therapy (100 mg/kg/dose) used in combination with TPE [39, 40, 66].

#### **6.1. Therapeutic plasma exchange**

Though often referred to simply as "plasmapheresis," the procedure utilized in the treatment of AMR is more accurately described as therapeutic plasma exchange (TPE). While plasmapheresis [42] technically describes plasma removal without replacement, TPE entails plasma removal with replacement of a substitute colloid component. A 1–1.5 L plasma volume exchange generally removes approximately 70% of plasma components, including anti-HLA antibodies [43]. For immunoglobulins, the durability this treatment differs dependent upon the tissue compartments in which each immunoglobulin subclass resides. IgM, which resides solely in the intravascular space, and does not significantly repopulate by re-equilibration following TPE, much unlike IgG and IgA. Re-equilibration into the intravascular space generally means that for IgG present in high concentration initially in the serum, multiple TPE treatments are required to make measurable impact on the circulating concentration [44–46]. Rates of antibody removal with TPE, as well as characteristics of rebound following treatment vary with antibody subclass and specificity, and mechanistically this remains poorly understood [47]. TPE was one of the first reported successful strategies for treatment AMR and remains a cornerstone of most current treatment protocols [37, 38, 48, 49].
