The Preliminary Results of Bortezomib Used as A Primary Treatment for An Early Acute Antibody-Mediated Rejection after Kidney Transplantation—A Single-Center Case Series

Abstract

Proteasome inhibitor bortezomib has been used in the treatment of refractory cases of acute and chronic antibody-mediated rejection (AMR) in kidney transplant recipients. However, its efficacy and safety as a primary treatment for early AMR has been scarcely investigated. We herein present our preliminary experience with bortezomib- and plasmapheresis-based primary treatment for early AMR. Thirteen patients transplanted between October 2015 and September 2019 were treated (starting at median 19th post-transplant day) with bortezomib/plasmapheresis protocol for early biopsy-proven AMR. Twelve out of thirteen patients received 4 doses and one patient recieved 3 doses of bortezomib (1.3 mg/m2 per dose). In 11/13 patients, 4–7 concomitant plasmapheresis sessions were performed, with or without intravenous immunoglobulin (IVIG). Of note, rituximab was not used in all study patients. The kidney graft and patient survival were 100%. The mean 3-month estimated glomerular filtration rate (eGFR) was 55.3 (95%CI: 44.9–65.8) mL/min/1.73m2, 8/13 patients completed 12-month follow-up with mean eGFR 60.4 (45.4–75.4) mL/min/1.73m2, and 6/13 patients completed a 24-month follow-up period with mean eGFR 73.9 (56.7–91.1) mL/min/1.73m2. Neutropenia < 1 G/L was observed in one patient, third or fourth grade thrombocytopenia in two patients, and eleven patients needed a blood transfusion (median: 2 units/patient). The mid-term results of a primary bortezomib-based treatment for kidney AMR showed its non-inferiority as compared to preceding regimens and acceptable safety. However, our data should be validated in a multicenter randomized trial.

The Korean Organ Transplantation Registry (KOTRY): an overview and summary of the kidney-transplant cohort

“…Older recipient age, cardiovascular disease, lower graft function, and DDKT are well-known risk factors for patient death in kidney transplant in previous studies [22][23][24], and Gonzalez-Molina et al [25] reported that treatment with mycophenolate mofetil and the use of tacrolimus instead of cyclosporine reduced the risk of patient death by 43%. In addition, although there are scarce data of the effect of bortezomib use on mortality in kidney transplantation, several previous studies have reported a higher incidence of adverse events, such as infectious disease, gastrointestinal and hematologic toxicity for bortezomib use in kidney transplantation [26][27][28]. Independent risk factors for graft loss were as follows: no antimetabolite drugs used at discharge, a higher serum creatinine concentration at discharge, and episodes of acute T-cell-mediated or antibody-mediated rejection.…”

“…The names of the participating hospitals and principal investigators of the KOTRY kidney cohort are as follows: Myoung Soo Kim 1 , Jaeseok Yang 2 , Jin Min Kong 3 , Oh Jung Kwon 4 , Deok Gie Kim 5 , Cheol Woong Jung 6 , Yeong Hoon Kim 7 , Joong Kyung Kim 8 , Chan-Duck Kim 9 , Ji Won Min 10 , Sung Kwang Park 11 , Yeon Ho Park 12 , Jae Berm Park 13 , Jung Hwan Park 14 , Jong-Won Park 15 , Tae Hyun Ban 16 , Sang Heon Song 17 , Seung Hwan Song 18 , Ho Sik Shin 19 , Chul Woo Yang 20 , Hye Eun Yoon 21 , Kang Wook Lee 22 , Dong Ryeol Lee 23 , Dong Won Lee 24 , Jieun Oh 25 , Sang-Ho Lee 26 , Su Hyung Lee 27 , Yu Ho Lee 28 , Jung Pyo Lee 29 , Jeong-Hoon Lee 30 , Jin Seok Jeon 31 , Heungman Jun 32 , Kyung Hwan Jeong 33 , Ku Yong Chung 34 , Man Ki Ju, https://orcid.org/0000-0002-4112-7003 Dong-Wan Chae, https://orcid.org/0000-0001-9401-892X Soo Jin Na Choi, https://orcid.org/0000-0002-0179-731X Myoung Soo Kim, https://orcid.org/0000-0002-8975-8381 Jung-Hwa Ryu, https://orcid.org/0000-0002-1648-624X Jong Cheol Jeon, https://orcid.org/0000-0003-0301-7644 Curie Ahn, https://orcid.org/0000-0001-7033-1102 Jaeseok Yang, https://orcid.org/0000-0002-5378-7797…”

Quick preparation of ABO‐incompatible living donor liver transplantation for acute liver failure

“…According to the results in this study, the dosage of the bortezomib may have to increase, or aggressive plasma exchange to reduce isoagglutinin should be performed if isoagglutinin rebound after transplantation. In the literature, four or more doses of bortezomib were most adopted in desensitization protocol or in treating antibody‐mediated rejection 22–24 . However, bortezomib is associated with adverse effects of anemia, thrombocytopenia, fatigue, dyspnea and gastrointestinal toxicity.…”

“…However, bortezomib is associated with adverse effects of anemia, thrombocytopenia, fatigue, dyspnea and gastrointestinal toxicity. In Kolonko's study, 11 of 13 patients needed blood transfusion after four doses of bortezomib for antibody‐mediated rejection treatment 22 . Hence, the suitable doses of bortezomib might be between one and four.…”

Optimal Immunosuppression Strategy in the Sensitized Kidney Transplant Recipient

“…Bortezomib has been shown to be effective in preventing AMR and ACR, as well as reducing DSA in kidney transplant recipients [150]. Since then, bortezomib has been studied in combination therapy with plasmapheresis (PP) and IVIG with or without rituximab or steroid as plasma cell-targeted therapy in sensitized kidney transplant recipients, showing success in reducing DSA, treating acute or late AMR [151,152] as rescue or primary treatment [153][154][155], and reducing plasma cell rich acute rejection [156,157]. Recently, six patients who developed acute AMR received bortezomib and belatacept combination therapy, which led to the reversal of AMR and reduction in circulating DSA [158].…”