A Randomized Trial of Bortezomib in Late Antibody-Mediated Kidney Transplant Rejection

J Am Soc Nephrol. 2018 Feb;29(2):591-605. doi: 10.1681/ASN.2017070818. Epub 2017 Dec 14.


Late antibody-mediated rejection (ABMR) is a leading cause of kidney allograft failure. Uncontrolled studies have suggested efficacy of the proteasome inhibitor bortezomib, but no systematic trial has been undertaken to support its use in ABMR. In this randomized, placebo-controlled trial (the Bortezomib in Late Antibody-Mediated Kidney Transplant Rejection [BORTEJECT] Trial), we investigated whether two cycles of bortezomib (each cycle: 1.3 mg/m2 intravenously on days 1, 4, 8, and 11) prevent GFR decline by halting the progression of late donor-specific antibody (DSA)-positive ABMR. Forty-four DSA-positive kidney transplant recipients with characteristic ABMR morphology (median time after transplant, 5.0 years; pretransplant DSA documented in 19 recipients), who were identified on cross-sectional screening of 741 patients, were randomly assigned to receive bortezomib (n=21) or placebo (n=23). The 0.5-ml/min per 1.73 m2 per year (95% confidence interval, -4.8 to 5.8) difference detected between bortezomib and placebo in eGFR slope (primary end point) was not significant (P=0.86). We detected no significant differences between bortezomib- and placebo-treated groups in median measured GFR at 24 months (33 versus 42 ml/min per 1.73 m2; P=0.31), 2-year graft survival (81% versus 96%; P=0.12), urinary protein concentration, DSA levels, or morphologic or molecular rejection phenotypes in 24-month follow-up biopsy specimens. Bortezomib, however, associated with gastrointestinal and hematologic toxicity. In conclusion, our trial failed to show that bortezomib prevents GFR loss, improves histologic or molecular disease features, or reduces DSA, despite significant toxicity. Our results reinforce the need for systematic trials to dissect the efficiency and safety of new treatments for late ABMR.

Keywords: antibody-mediated rejection; bortezomib; chronic allograft failure; kidney; randomized controlled trial; transplantation.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Allografts / immunology
  • Antibodies / blood
  • Bortezomib / adverse effects
  • Bortezomib / therapeutic use*
  • Disease Progression
  • Double-Blind Method
  • Female
  • Glomerular Filtration Rate
  • Graft Rejection / complications
  • Graft Rejection / pathology
  • Graft Rejection / physiopathology*
  • Graft Rejection / prevention & control*
  • Graft Survival
  • HLA Antigens / immunology*
  • Humans
  • Kidney Transplantation*
  • Male
  • Middle Aged
  • Prospective Studies
  • Proteasome Inhibitors / adverse effects
  • Proteasome Inhibitors / therapeutic use*
  • Proteinuria / etiology
  • Time Factors
  • Treatment Failure


  • Antibodies
  • HLA Antigens
  • Proteasome Inhibitors
  • Bortezomib