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

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

#### **6.4. Splenectomy**

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 beneficial in select patient situations [72].

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

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 improved outcomes with the addition of rituximab [82].

Whereas the postulated effect of rituximab on antibody-production is indirect, bortezomib (Velcade®, Takeda Oncology) acts directly at the level of the antibody-producing plasma cell. Bortezomib is a proteasomal inhibitor that depletes circulating plasma cells by inducing apoptosis [83–85]. The first reported use bortezomib in transplant recipients was in a small series where graft salvage was attempted in the cases of AMR refractory to therapies including TPE, IVIG, and rituximab [86]. Following bortezomib therapy, circulating DSA strength has been reported to decrease substantially [87], though interestingly, class I and class II DSAs may be not be reduced with equal efficacy [88]. Bortezomib, like rituximab, has been used in combination with TPE, with and without steroids and rituximab [89–92] and is thoroughly reviewed elsewhere [85].

**7. Outcomes and unanswered questions**

Generally reported estimates of the incidence of AMR are around 7% for all recipients [108], and may be as high as 50% among recipients of HLA-incompatible grafts [109, 110]. Despite improved abilities to diagnose and treat AMR, it remains an important cause of premature graft loss [111, 112]. Clinically silent AMR identified on biopsy in the setting of normal renal function, if left untreated, is associated with a two-fold increased risk of graft loss [109, 113]. If the AMR is clinically apparent and associated with graft dysfunction, the risk of graft loss can increase to six-fold [109]. Even when recognized and treated promptly, AMR portends recur-

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

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The pathophysiology of AMR and the molecular mechanisms of antibody-mediated injury have never been better understood, however the fact that such heterogeneity is observed clinically from case to case suggests that much remains yet to be clarified. The spectrum of AMR severity, acuity, and treatability is broad and not easily predictable even when clinical parameters appear relatively constant. While some lines of evidence suggest that any DSA [116, 117] even historical DSA not present at transplant [111], has the potential to be harmful, others have reported clinically silent DSA that, although detectable, has no apparent impact the incidence of rejection or on long-term outcomes [118]. Whether sensitization alone, not just DSA, is an independent risk factor for AMR, is unclear [115]. Whether this variability lies in the DSA specificity, in differential expression of the target HLA molecules on the allograft, or on other factors, remains to be determined. Multiple lines of evidence suggest that complement activating, C1qbinding DSA are associated with greater risks for rejection and for worse outcomes [119–122], compared to non-C1q binding DSAs. The ability to identify and test for the more virulent DSAs may prove to be of benefit in terms of surveillance and directing treatment. There is evidence that class II DSA is associated with worse long-term outcomes [123–125], and poorer responses to treatments [126] compared to class I DSAs. What underlies this difference, remains uncertain. Whether, and how, antigens vary in terms of their immunogenicity and risks for inciting AMR, remains to be determined. Whether any of the available therapies is optimally suited for different DSA patterns or specificities, or AMR phenotypes, also remains to be determined. Perhaps the most effective means of minimizing the risks of AMR may be in maximizing efforts to prevent it. Experience with HLA-incompatible transplant recipients have demonstrated, both in single-center and multi-center series, that long-term outcomes are inversely correlated with the starting crossmatch strength [19, 20]. Thus careful attention paid to donor selection, and making any effort possible to minimize incompatibility, can pay great dividends in the long-term post-transplant [115]. And while prevention will not always be feasible, the ability to more readily and accurately detect AMR will enable more rapid treatments and improve the chances of their success. Just as new agents are being developed to remove antibody [127], and interrupt the pathways that impart antibody-mediated injury, so too are innovative, increasingly specific, and less invasive procedures for the diagnosis of AMR. The ability to identify AMR, and perhaps even characterize AMR phenotypes based on gene expression profiles in biopsy tissue [128, 129] should allow a clearer determination of AMR severity and ultimately help guide therapy. The identification of serum and/or urinary biomarkers [130–133] should enable better surveillance, earlier diagnosis of AMR, and

rent AMR, and ultimately, chronic AMR and transplant glomerulopathy [114, 115].

#### **6.6. Complement inhibition**

The realization that the tissue injury associated with AMR was, at least in part, mediated by the complement cascade led to the hypothesis that complement inhibition may afford tissue-level protection while TPE or other antibody removing techniques were implemented. The first reported use of the terminal complement inhibitor eculizumab (Soliris®, Alexion Pharmaceuticals) was in a patient with severe accelerated oliguric AMR who was deemed an inappropriate candidate for a rescue splenectomy [93]. With TPE, IVIG, rituximab, and eculizumab, recovery of renal function was achieved. Several reports describe the use of eculizumab as a salvage therapy, either in lieu of or in combination with splenectomy [94–96], but reports of successful salvage are not universal [97]. Eculizumab's mechanism of action of action led to studies of its pre-emptive use in incompatible kidney recipients at high risk for AMR, and while eculizumab may decrease the incidence of AMR [98], it does not prevent it [99].

Additional complement inhibitors have since become available and are being evaluated for their relative efficacy in AMR. C1-esterase inhibitor (C1-INH) is an endogenous protein that is a more proximal inhibitor of the complement cascade and is commercially available as a purified plasma preparation (Berinert®, CSL Behring, and Cinryze®, Shire). A recently reported double-blinded randomized controlled trial of C1-INH as an add-on to standard TPE therapy for AMR suggested a benefit in terms of improved long term renal allograft function in those who received C1-INH [100]. Like eculizumab, C1-INH may have promise in the prevention of AMR in high-risk patients [101], or as a graft protective agent in the setting of severe or treatment refractory AMR [102].

#### **6.7. IL-6 inhibition**

IL-6 is a pro-inflammatory cytokine with properties that activate numerous cell lines including B-T- and plasma cells. Tocilizumab (Actemra®, Genentech)is a humanized monoclonal antibody which blocks IL-6 signal transduction by binding and inhibiting the IL-6 receptor [103]. In animal models, IL-6/IL-6R signaling has been found to promote renal injury [104] and may be associated with the injury of acute rejection [105]. In human studies, it may affect a decrease in HLA antibody production [106]. A recent trial of tocilizumab in patients with refractory chronic AMR reported improved long-term graft survival rates in those who received tocilizumab [107].
