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

Abstract

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.

Copyright © 2018 by the American Society of Nephrology.

Figures

Graphical abstract

Figure 1.

Study flow chart. Cross-sectional ABMR screening of 741 prevalent kidney transplant recipients (part A of the study) identified 45 patients eligible for inclusion in the interventional part of the trial (part B). One recipient withdrew consent shortly after randomization and did not receive trial treatment. Twenty-three patients received placebo, and 21 patients received bortezomib. Two patients died during follow-up, and the other 42 recipients completed the study. TCMR, T cell–mediated rejection.

Figure 2.

Bortezomib did not affect kidney allograft function. (A) Individual eGFR course (dashed lines) and mean eGFR (solid lines) computed from the mixed model for the primary analysis and (B) comparison between bortezomib and placebo for median levels of eGFR. Analyses are on the basis of serial eGFR measurements at 0, 6, 12, 18, and 24 months (for patient death or return to dialysis, no data were imputed). Box plots indicate the median, the interquartile range, the minimum, and the maximum of the measures.

Figure 3.

Study groups did not significantly differ in Kaplan–Meier patient and graft survival. (A) Overall graft survival, (B) death-censored graft survival, and (C) patient survival are shown in relation to treatment allocation. The Mantel Cox log rank test was used to compare survival rates between groups.

Figure 4.

Study groups did not significantly differ in terms of percentage change in DSA MFI from baseline. Individual and pooled MFI changes are illustrated for (A) the MFI_max and (B) the sum of MFI of all detected DSAs (MFI_sum). Box plots indicate the median, the interquartile range, the minimum, and the maximum of the measures. Outliers are indicated as circles.

Figure 5.

Study groups did not differ in ABMR phenotypes. (A) ABMR categories and (B) C4d scoring results in index and 24-month follow-up biopsies are shown in relation to treatment allocation. Absolute and relative numbers of patients are provided for each category. ABMR and C4d staining were categorized following the rules of the Banff scheme. Six study participants did not undergo follow-up biopsy (patient death or dialysis: n=4; biopsy was contraindicated: n=1; lack of consent: n=1). Bx, biopsy.

Figure 6.

Study groups did not significantly differ in adverse event-free survival. Kaplan–Meier AE- and SAE-free survival rates are shown for bortezomib- and placebo-treated patients. The Mantel Cox log rank test was used to compare study groups.