The role of proteasome inhibition with bortezomib in the treatment of antibody-mediated rejection after kidney-only or kidney-combined organ transplantation.
BACKGROUND
We report our initial experience in using the proteasome inhibitor, bortezomib, to treat established antibody-mediated rejection (AMR) in 20 patients.


METHODS
There were 16 kidney-only and 4 kidney-combined organ recipients with de novo donor-specific antibody (DSA) and histologic evidence of AMR with peritubular capillaries C4d deposition. AMR was diagnosed 19.8 months (range 1-71 months) posttransplant. Patients received intravenous corticosteroids followed by a 2-week cycle on days 1-4-8-11 of plasmapheresis and 1.3 mg/m² bortezomib; then 0.5 mg/kg intravenous immunoglobulin four times.


RESULTS
De novo class I DSA was detected in 11 (55%) and class II DSA in 18 (90%) recipients. The absolute mean difference between peak-nadir dominant DSA was 68,171 molecules of equivalent soluble fluorochrome (P<0.0001), representing 55%±22%. Only two patients (10%) had undetectable DSA after treatment. Patient survival is 100%, and graft survival is 85% with a mean follow-up of 9.8 months (range 2-20 months). The treatment was generally well tolerated but caused fatigue, gastrointestinal complaints, fluid retention, and thrombocytopenia in a number of patients. The last follow-up estimated glomerular filtration rate was 41.9±16.8 mL/min (range 20.6-72.2 mL/min). However, only 25% returned to their baseline renal function before AMR, and many have proteinuria with urine protein/creatinine more than 0.5 in 41% and more than 1.0 in 18%.


CONCLUSIONS
The bortezomib-containing regimen demonstrated activity in AMR but seems to be most effective before the onset of significant renal dysfunction (serum creatinine <3 mg/dL) or proteinuria (<1 g/day). The best use of bortezomib to treat AMR should be evaluated in controlled trials using dosing strategies that include longer courses or retreatment schedules.
Glickman Urological and Kidney Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA. flechns@ccf.org
Stuart M
SM
Flechner
Richard
R
Fatica
Medhat
M
Askar
Brian R
BR
Stephany
Emilio
E
Poggio
Anna
A
Koo
Stacey
S
Banning
Andres
A
Chiesa-Vottero
Titte
T
Srinivas
D000206:Actuarial Analysis; D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000918:Antibody Specificity; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D003131:Combined Modality Therapy; D003404:Creatinine / Q000097:blood; D005260:Female; D006084:Graft Rejection / Q000188:drug therapy* / Q000276:immunology; D006085:Graft Survival / Q000502:physiology; D006801:Humans; D007518:Isoantibodies / Q000276:immunology*; D016030:Kidney Transplantation / Q000276:immunology* / Q000401:mortality; D016031:Liver Transplantation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D016035:Pancreas Transplantation / Q000276:immunology; D010956:Plasmapheresis; D011480:Protease Inhibitors / Q000627:therapeutic use*; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000627:therapeutic use*
D000305:Adrenal Cortex Hormones; D001897:Boronic Acids; D007518:Isoantibodies; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D003404:Creatinine