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• W2095409106 abstract "Calcineurin inhibitors (CNI) are a cornerstone of maintenance immunosuppression in kidney transplantation. Although CNIs have reduced rejection rates and improved 1-year allograft survival, long-term allograft survival has not improved (1–3). Calcineurin inhibitor adverse effects include hypertension, hyperglycemia, and nephrotoxicity (3–5). Sirolimus, an alternative to CNIs, has toxicities including proteinuria, hyperlipidemia, and delayed wound healing (3, 6, 7). Belatacept, a selective costimulation blocker, inhibits T cell activation through binding of B7 ligands on antigen presenting cells (APC) (8–10). In phase II and III trials of belatacept as part of de novo immunosuppression regimens in kidney transplant, belatacept was associated with better renal function and less chronic allograft nephropathy compared to cyclosporine and was also found to have similar graft and patient survival (8, 10–12). No studies or case reports to date have evaluated switching to belatacept immediately following the diagnosis of acute rejection (13). Antibody-mediated rejection (AMR) can develop early or late posttransplant. Often late-AMR occurs after inadequate immunosuppression (14, 15). Recently, bortezomib-based regimens have been found to be effective in the treatment of AMR (15, 16). The following case report from the University of Cincinnati and Christ Hospitals in Cincinnati describes the treatment of concomitant acute and chronic AMR with bortezomib-based therapy and simultaneous conversion from sirolimus to belatacept. CASE REPORT A 36-year-old man with end-stage renal disease secondary to IgA nephropathy underwent living-related renal transplant in May 1995. The patient did well with no acute rejection for 15 years. Serum creatinine (Scr) nadir after transplant was 1.2 mg/dL. The patient was receiving cyclosporine, prednisone, and azathioprine. In May 2006, a biopsy demonstrated chronic CNI toxicity (Scr, 1.7 mg/dL). Patient was converted from cyclosporine to sirolimus. His Scr remained stable (1.5 and 1.6 mg/dL). In September 2008, a biopsy demonstrated moderate chronic transplant glomerulopathy on light and electron microscopy (Scr, 2.06 mg/dL). DSA were detected at that time (A11: 390,000 MESF [5342 MFI]), but C4d staining in pertitubular capillaries (PTC) was negative. No changes were made to his immunosuppression. Figure 1 illustrates DSA trend.FIGURE 1: DSA before AMR treatment from September 2008 to March 2012.In January 2012, proteinuria was noted (urine protein/creatinine ratio of 5.4) and persisted despite the initiation of candesartan. A biopsy in May 2012 revealed acute AMR with diffuse C4d staining of the PTCs, peritubular capillaritis, and evidence of chronic transplant glomerulopathy. Bortezomib-based AMR therapy was initiated (rituximab, bortezomib, and plasmapheresis). Sirolimus was discontinued, and belatacept was initiated. Follow-up biopsy 13 days later revealed improvement in C4d PTC staining, decreased DSA, and improved Scr. Figure 2 illustrates DSA during rejection therapy.FIGURE 2: DSA at AMR treatment initiation to last follow-up May 2012 to August 2012.Three months later, Scr had improved to 1.9 mg/dL, and urine protein/creatinine ratio was 2.5. DSA remained stable (A11: 7900 MFI). DISCUSSION Data on late conversion from traditional maintenance immunosuppression to belatacept are limited. A previously published case report discussed successful conversion to belatacept after recurrent thrombotic microangiopathy from cyclosporine, tacrolimus, and sirolimus (17). The largest conversion trial to date randomized stable renal transplant patients to continue a CNI-based regimen or switch to a belatacept-based regimen (13). Belatacept binds the B7 ligands on APCs thereby preventing T-cell activation. This step is vital for T-cell activation and proliferation; without it interleukin-2 production is inhibited, leading to cell activation attenuation (8, 9, 11, 18). There are no published reports on using bortezomib for rejection in patients on belatacept. Traditional therapies for AMR include IVIg, plasmapheresis, rituximab, and antithymocyte globulin, none of which deplete plasma cells (16). Recently, bortezomib has been used as a means for targeting plasma cells (16, 19). Several publications have found that bortezomib-based regimens are capable of reversing AMR (15, 16, 19). To date, reported experiences with bortezomib therapy for AMR have been under tacrolimus-based immunosuppression. The present case is unique as it provides evidence for bortezomib-based therapy under belatacept-based immunosuppression. These observations, although limited to a single patient, are important, as the use of belatacept-based immunosuppression increases across transplant centers. Plasma cell populations consists of immature plasmablasts and mature long-lived plasma cells. Emerging data on CD28 and plasma cell function indicates that CD28-derived signals may play a role in long-term plasma cell survival (20). Njau and colleagues noted that CD28 is expressed on both murine and human plasma cells, but its function is not entirely clear. In murine models, the CD28-B7 ligand interaction was shown to influence plasma cell survival and antibody production; the loss of CD28 signaling resulted in upregulation of plasma cell antibody production (20). In summary, this patient successfully transitioned to belatacept therapy, while being treated with bortezomib for acute AMR. Follow-up biopsy documented improvement in histologic changes of AMR; DSAs have been reduced and are now stable. The patient’s renal function improved and remained stable. This report presents the first experience with bortezomib-based therapy under belatacept-based immunosuppression. Jill C. Krisl 1 Rita R. Alloway2 Adele Rike Shields3 Michael A. Cardi4 E. Steve Woodle5 1 Work created as Transplant Pharmacy Fellow, Department of Surgery, Division of Transplantation, University of Cincinnati Academic Health Center, Cincinnati, OH 2 Transplant Clinical Research, University of Cincinnati Medical Center, Cincinnati, OH 3 Transplant Clinical Pharmacy, The Christ Hospital, Cincinnati, OH 4 Director of Kidney Transplantation, The Christ Hospital, Kidney and Hypertension Center, Cincinnati, OH 5 Director Division of Transplantation Department of Surgery, University of Cincinnati Medical Center, Cincinnati, OH" @default.
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• W2095409106 date "2014-02-27" @default.
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• W2095409106 title "Bortezomib-Based Antibody-Mediated Rejection Therapy and Simultaneous Conversion to Belatacept" @default.
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