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

Abstract

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.