The lack of Lazarus effect with proteasome inhibition

Abstract

There have been marked improvements in the short-and long-term outcomes for children after renal transplantation over the past two decades with superior quality and quantity of life. It is encouraging to see increased patient and renal allograft survival rates with initially lower acute renal allograft rejection rates due to improved matching and immunosuppressive regimens. Unfortunately, longer-term renal allograft survival remains unchanged with chronic allograft injury from both immune and non-immune causes, resulting in chronic allograft dysfunction, morbidity from chronic kidney disease, and eventual renal allograft loss. Acute and chronic antibody-mediated rejection remains a clinical dilemma with a growing evidence base of its treatment, including proteasome inhibition using intravenous bortezomib. The future goal is to reduce chronic allograft dysfunction and make renal transplants last longer for pediatric renal transplant recipients who may require retransplantation during their childhood and adult lives, which can become successively more difficult due to sensitization.

Carfilzomib: Looking for ‘The Holy Grail’ to treat antibody‐mediated rejection

“…5,6 Bortezomib is a first-generation proteasome inhibitor (PI) which induces apoptosis of mature plasma cells to further inhibit generation of new antibodies. 7 In a retrospective study of pediatric kidney transplant recipients (KTR) treated for AMR with plasmapheresis, IVIg and rituximab, bortezomib showed only short stabilization of renal allograft function with estimated glomerular filtration rate (eGFR) and short-term effect on donor-specific antibody (DSA) mean fluorescent intensity (MFI). 8 The first RCT conducted in a cohort of 44 adult KTR demonstrated no difference in the two groups in the eGFR, the urine protein: creatinine ratio and the morphologic rejection phenotypes on biopsy at 24 months follow-up.…”