Yonsei Med J.  2015 Nov;56(6):1638-1642. 10.3349/ymj.2015.56.6.1638.

The Effect of Bortezomib on Antibody-Mediated Rejection after Kidney Transplantation

• Lee J
• Kim BS
• Park Y
• Lee JG
• Lim BJ
• Jeong HJ
• Kim YS
• Huh KH

• KMID: 2345894
• DOI: http://doi.org/10.3349/ymj.2015.56.6.1638

Abstract

PURPOSE
Recently, bortezomib has been used to treat antibody-mediated rejection (AMR) refractory to conventional treatment such as plasmapheresis, intravenous immunoglobulin, and rituximab. The authors aimed to describe their experiences when bortezomib was used to treat refractory AMR.
MATERIALS AND METHODS
Eleven refractory AMR episodes treated with bortezomib were included in this study. The patients received one or two cycles of bortezomib (1.3 mg/m2) on days 1, 4, 8, and 11.
RESULTS
Bortezomib effectively reduced antibodies against various targets, including human leukocyte antigen (HLA) class I and II, ABO blood group antigen, and angiotensin II type 1 receptor. Antibodies were depleted or reduced significantly in eight AMR episodes. Overall, there was a significant improvement in the mean estimated glomerular filtration rate (eGFR) at 3 months after therapy (36.91+/-22.15 mL/min/1.73 m2) versus eGFR at time of AMR diagnosis (17.00+/-9.25 mL/min/1.73 m2; p=0.007). All six early-onset AMR episodes (within 6 months post-transplantation) showed full recovery of allograft function. Additionally, three of the five late-onset AMR episodes (>6 months post-transplantation) showed improved allograft function.
CONCLUSION
Anti-humoral treatment based on bortezomib might be an effective strategy against refractory AMR caused by various types of antibodies. Notably, this treatment could be more effective in early-onset AMR than in late-onset AMR.

Keyword

Angiotensin II type 1 receptor antibodies; antibody-mediated rejection; bortezomib; HLA antibodies; kidney transplantation

MeSH Terms

Adolescent
Adult
Antibodies, Monoclonal/therapeutic use
Antineoplastic Agents/*therapeutic use
Boronic Acids/therapeutic use
Bortezomib/*therapeutic use
Female
Graft Rejection/*drug therapy/*prevention & control
Humans
Immunoglobulins, Intravenous/therapeutic use
Immunologic Factors/therapeutic use
Isoantibodies
Kidney Failure, Chronic/*surgery
*Kidney Transplantation
Male
Middle Aged
Plasmapheresis
Pyrazines/administration & dosage
Transplantation, Homologous
Antibodies, Monoclonal
Antineoplastic Agents
Boronic Acids
Bortezomib
Immunoglobulins, Intravenous
Immunologic Factors
Isoantibodies
Pyrazines

Figure

• 

  Fig. 1 1. Changes of renal allograft function after bortezomib treatment according to AMR onset time. AMR, antibody-mediated rejection; Dx, diagnosis; mo, months.

Reference

1. Sellarés J, de Freitas DG, Mengel M, Reeve J, Einecke G, Sis B, et al. Understanding the causes of kidney transplant failure: the dominant role of antibody-mediated rejection and nonadherence. Am J Transplant. 2012; 12:388–399.

2. Djamali A, Kaufman DB, Ellis TM, Zhong W, Matas A, Samaniego M. Diagnosis and management of antibody-mediated rejection: current status and novel approaches. Am J Transplant. 2014; 14:255–271.

3. Ejaz NS, Alloway RR, Halleck F, Dürr M, Budde K, Woodle ES. Review of bortezomib treatment of antibody-mediated rejection in renal transplantation. Antioxid Redox Signal. 2014; 21:2401–2418.

4. Walsh RC, Alloway RR, Girnita AL, Woodle ES. Proteasome inhibitor-based therapy for antibody-mediated rejection. Kidney Int. 2012; 81:1067–1074.

5. Walsh RC, Brailey P, Girnita A, Alloway RR, Shields AR, Wall GE, et al. Early and late acute antibody-mediated rejection differ immunologically and in response to proteasome inhibition. Transplantation. 2011; 91:1218–1226.

6. Yang KS, Jeon H, Park Y, Jo IH, Kim JI, Moon IS, et al. Use of bortezomib as anti-humoral therapy in kidney transplantation. J Korean Med Sci. 2014; 29:648–651.

7. Kim MG, Kim YJ, Kwon HY, Park HC, Koo TY, Jeong JC, et al. Outcomes of combination therapy for chronic antibody-mediated rejection in renal transplantation. Nephrology (Carlton). 2013; 18:820–826.

8. Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008; 111:2516–2520.

9. Gupta G, Abu Jawdeh BG, Racusen LC, Bhasin B, Arend LJ, Trollinger B, et al. Late antibody-mediated rejection in renal allografts: outcome after conventional and novel therapies. Transplantation. 2014; 97:1240–1246.

10. Philogene MC, Sikorski P, Montgomery RA, Leffell MS, Zachary AA. Differential effect of bortezomib on HLA class I and class II antibody. Transplantation. 2014; 98:660–665.

11. Gertz MA. Immunoglobulin light chain amyloidosis: 2014 update on diagnosis, prognosis, and treatment. Am J Hematol. 2014; 89:1132–1140.

12. Neubert K, Meister S, Moser K, Weisel F, Maseda D, Amann K, et al. The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis. Nat Med. 2008; 14:748–755.

13. Mengel M, Sis B, Haas M, Colvin RB, Halloran PF, Racusen LC, et al. Banff 2011 Meeting report: new concepts in antibody-mediated rejection. Am J Transplant. 2012; 12:563–570.

14. Yoo S, Lee EY, Huh KH, Kim MS, Kim YS, Kim HO. Role of plasma exchange in ABO-incompatible kidney transplantation. Ann Lab Med. 2012; 32:283–288.

15. Westphal S, Hansson S, Stelin G, Holgersson J, Mjörnstedt L, Friman S. Successful treatment of severe ABO antibody-mediated rejection using bortezomib: a case report. Transplant Proc. 2013; 45:1213–1215.

16. Loupy A, Lefaucheur C, Vernerey D, Prugger C, Duong van Huyen JP, Mooney N, et al. Complement-binding anti-HLA antibodies and kidney-allograft survival. N Engl J Med. 2013; 369:1215–1226.

17. Gloor JM, Sethi S, Stegall MD, Park WD, Moore SB, DeGoey S, et al. Transplant glomerulopathy: subclinical incidence and association with alloantibody. Am J Transplant. 2007; 7:2124–2132.

18. Loupy A, Hill GS, Suberbielle C, Charron D, Anglicheau D, Zuber J, et al. Significance of C4d Banff scores in early protocol biopsies of kidney transplant recipients with preformed donor-specific antibodies (DSA). Am J Transplant. 2011; 11:56–65.