Refractory Antibody-mediated Rejection Research Articles

The Use of Bortezomib as a Rescue Treatment for Acute Antibody-Mediated Rejection: Report of Three Cases and Review of Literature

Antibody-mediated rejection (AMR) typically occurs early after transplantation in approximately 5%–7% of recipients. The literature reports suggest that 12%–37% of kidney transplant recipients with acute AMR do not respond to treatment and eventually lose their grafts. The proteasome inhibitor bortezomib is currently approved by the Food and Drug Administration for the treatment of multiple myeloma. It has been demonstrated both in vitro and in vivo to possess apoptotic properties against mature plasma cells. Herein we have described a series of 3 patients with positive cross-matches who developed early AMR after kidney transplantation. Bortezomib rescue treatment was administered after the patients failed to respond to plasmapheresis/intravenous immunoglobulin and splenectomy. All 3 patients responded with full, durable recovery of renal function. In conclusion, bortezomib is useful to treat refractory AMR after kidney transplantation.

Treatment of Refractory Anti-HLA Antibody-Mediated Rejection with Eculizumab in An Adult with Combined Liver and Small Bowel Transplantation

The importance of antibody-mediated rejection (AMR) in the outcome of intestinal grafts, like other solid organs, has become a major challenge to avoid graft failure. The therapeutic options are limited, invasive and may have significant side effects. We report the case of a 62-year-old Caucasian woman who received a combined liver and small bowel allograft for intestinal failure-associated liver disease in June 2011. Three months after transplantation the patient presented with refractory AMR and received salvage eculizumab therapy, a complement protein C5 antibody that inhibits the formation of the membrane attack complex (MAC), combined with PP/IVIg. Three months after beginning eculizumab, the patient's oral nutritional intake and physical condition improved significantly. Subsequent endoscopies and histologies showed complete restoration of mucosa with no vascular abnormalities and a marked decrease in the C5b-C9 MAC complex deposition in the small bowel. In our opinion, the marked improvement of both clinical and histological features shows that eculizumab can reverse acute AMR in small bowel transplantation.

Cell Population in Spleens During Antibody-Mediated Rejection

In the treatment of refractory antibody-mediated rejection (AMR), splenectomy has been associated with surprisingly rapid recovery of renal function. The mechanism is still unclear. We review 11 recipients, who underwent rescue splenectomy (RS) as a treatment of AMR within 3 months after kidney transplantation. At transplantation, all patients had undergone desensitization for initially positive crossmatch to their prospective donors. The cellular populations of the spleen were analyzed by immunohistochemistry. For comparison, we obtained spleen specimens from eight controls who were non-transplantation patients. Rejection occurred in all the patients early after transplantation (mean [SD], 7.1 [5.7] days). One graft was lost 4 weeks after kidney transplantation. A significantly higher number of plasma cells (PCs) (P=0.049) and lower number of T and B lymphocytes (P=0.02 and P=0.005, respectively) were detected in the RS group compared with the control group. By analyzing the PC variations in the RS group, significantly lower numbers of PCs were detected in the spleens of patients who received rituximab before splenectomy (P=0.0004). In contrast, a higher number of PCs were found in patients (n=3) who did not respond to splenectomy and subsequently underwent bortezomib treatment and recovered their renal function (P=0.02). Splenectomy may reverse AMR by debulking PCs. Our analysis suggests that patients with a very high load of PCs may not be rescued by splenectomy alone and may need additional treatments.

138 Bortezomib for Management of Antibody-Mediated Rejection Following Pediatric Heart Transplantation

Antibody-mediated rejection (AMR) is emerging as a major challenge to pediatric heart transplantation. Bortezomib, a proteaosome inhibitor, is now being used as an adjunct in the management of AMR. We report our experience with bortezomib to treat refractory AMR in children following heart transplantation.

Reversal of refractory antibody-mediated rejection in blood group incompatible kidney transplantation by Eculizumab

Reversal of refractory antibody-mediated rejection in blood group incompatible kidney transplantation by Eculizumab

Proteasome Inhibitor-Based Primary Therapy for Antibody-Mediated Renal Allograft Rejection

Rapid and complete elimination of donor-specific anti-human leukocyte antigen antibodies (DSA) during antibody-mediated rejection (AMR) is rarely achieved with traditional antihumoral therapies. Proteasome inhibitor-based therapy has been shown to effectively treat refractory AMR, but its use as a primary therapy for AMR has not been presented. Our initial experience with proteasome inhibition as a first-line therapy for AMR is presented. Adult kidney transplant recipients with AMR, diagnosed by Banff criteria, received a bortezomib-based regimen as the primary therapy. Bortezomib therapy was administered per package insert with plasmapheresis performed immediately before each bortezomib dose, and a single rituximab dose (375 mg/m2) given with the first bortezomib dose. DSA were quantitated using single-antigen beads on a Luminex platform. Two patients underwent bortezomib-based therapy for acute AMR occurring within the first 2 weeks after transplantation. High DSA levels and positive C4d staining of peritubular or glomerular capillaries were present at the time of diagnosis. Both patients experienced prompt AMR reversal and elimination of detectable DSA within 14 days of bortezomib-based therapy. Renal function remains excellent with normal urinary protein excretion at 5 and 6 months after AMR diagnosis. One patient experienced a repeated elevation of DSA (including two new human leukocyte antigen specificities) 2 months after initial bortezomib therapy, but without C4d deposition or histologic evidence of AMR. Retreatment with bortezomib provided prompt, complete, and durable DSA elimination. Proteasome inhibitor-based combination therapy provides a potential means for rapid DSA elimination in early acute AMR in renal transplant recipients.

A Single Low-Fixed Dose of Rituximab to Salvage Renal Transplants From Refractory Antibody-Mediated Rejection

Rituximab may improve graft survival in renal acute antibody-mediated rejection (AMR), but data confirming efficacy and optimal dosing is lacking. High-dose regimens may be associated with significant rates of infective complications. We therefore conducted a pilot study of a single low-fixed dose (500 mg) of rituximab in seven consecutive patients with AMR resistant to standard therapy. After a mean follow-up of 21 months (range, 9.5-33 months), graft and patient survival were 100% with serum creatinine levels significantly lower than peak rejection levels (171+/-73 micromol/L vs. 559+/-358 micromol/L, P=0.028). B cells were undetectable in all patients for more than or equal to 6 months and in six of seven patients for more than or equal to 12 months after rituximab. Three patients encountered a significant infective complication including cytomegalovirus reactivation, viral pneumonia, and polyoma viral nephropathy. All have since resolved. A single low-fixed dose of rituximab may help improve graft survival in AMR and offers the potential advantage of reduced infective complications.