The Effect of Bortezomib on the Management of Immediate Postoperative Refractory Antibody-Mediated Rejection after Kidney Transplantation

So-Jeong Kim; Kang-Woong Jun; Jeong-Kye Hwang; Byung-Ha Chung; Chul-Woo Yang; In-Sung Moon; Ji-il Kim; Mi-Hyeong Kim

doi:10.4285/jkstn.2018.32.3.49

Journal List > J Korean Soc Transplant > v.32(3) > 1101757

Go to TopGo to Top Go to BottomGo to Bottom

TOOLS

Kim, Jun, Hwang, Chung, Yang, Moon, Kim, and Kim: The Effect of Bortezomib on the Management of Immediate Postoperative Refractory Antibody-Mediated Rejection after Kidney Transplantation

Original Article

J Korean Soc Transplant 2018;32(3):49-56.

Published online: 19 January 2018

DOI: https://doi.org/10.4285/jkstn.2018.32.3.49

The Effect of Bortezomib on the Management of Immediate Postoperative Refractory Antibody-Mediated Rejection after Kidney Transplantation

So-Jeong Kim, M.D.¹, Kang-Woong Jun, M.D.¹, Jeong-Kye Hwang, M.D.¹, Byung-Ha Chung, M.D.², Chul-Woo Yang, M.D.², In-Sung Moon, M.D.¹, Ji-il Kim, M.D.¹, Mi-Hyeong Kim, M.D.^1,

¹Division of Vascular and Transplant Surgery, Department of Surgery, College of Medicine, The Catholic University of Korea, Seoul, Korea

²Division of Nephrology, Department of Internal Medicine², College of Medicine, The Catholic University of Korea, Seoul, Korea

Corresponding author: Mi-Hyeong Kim Division of Vascular and Transplant Surgery, Department of Surgery, St. Paul's Hospital, College of Medicine, The Catholic University of Korea, 180 Wangsan-ro, Dongdaemun-gu, Seoul 02559, Korea Tel: 82-2-961-4529, Fax: 82-2-960-4568 E-mail: mhkim@catholic.ac.kr

Received 30 March 2018 Revised 10 June 2018 Accepted 5 July 2018

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background:

Bortezomib has been used to treat antibody-mediated rejection (AMR) that usually develops after kidney transplantation (KT). Although it has been used in various clinical situations, it is difficult to precisely define how the drug affects the clinical course. We used bortezomib to treat eight cases of AMR that developed immediately following KT in patients who were resistant to conventional treatment.

Methods:

Eight cases of refractory AMR that developed immediately after KT were treated with bortezomib on days 1, 4, 8, and 11.

Results:

The resolution rate was 75%, and the 2-year rejection-free survival rate was 83%. Six cases underwent immunologically high-risk KT. Six recovering patients exhibited clinical improvement within 2 weeks of the first dose of bortezomib and recovered completely within 2 months. The effects of bortezomib seemed to be prolonged; only one additional rejection episode was observed. The two failed patients never exhibited any clinical improvement and progressed aggressively to graft failure soon after transplantation. Their donor specific anti-human leukocyte antigen antibody were sustained at high levels.

Conclusions:

Bortezomib is an effective rescue therapy in patients with AMR that developed immediately after KT.

Keywords: Bortezomib, Graft rejection, Immunosuppression, Kidney transplantation

REFERENCES

1). Everly MJ., Everly JJ., Susskind B., Brailey P., Arend LJ., Alloway RR, et al. Bortezomib provides effective therapy for antibody-and cell-mediated acute rejection. Transplantation. 2008. 86:1754–61.

2). Flechner SM., Fatica R., Askar M., Stephany BR., Poggio E., Koo A, et al. The role of proteasome inhibition with bortezomib in the treatment of antibody-mediated rejection after kidney-only or kidney-combined organ transplantation. Transplantation. 2010. 90:1486–92.

3). Nigos JG., Arora S., Nath P., Hussain SM., Marcus RJ., Ko TY, et al. Treatment of antibody-mediated rejection in kidney transplant recipients: a single-center experience with a bortezomib-based regimen. Exp Clin Transplant. 2012. 10:609–13.

4). Hardinger KL., Alford K., Murillo D. Bortezomib as rescue therapy for antibody mediated rejection: a single-center experience. Clin Transpl. 2010. 24:429–36.

5). Pavlakis M. Case presentations on two patients who received bortezomib for antibody mediated rejection at BIDMC. Clin Transpl. 2009. 23:343–5.

6). Hardinger KL., Alford K., Murillo D. Bortezomib for acute humoral rejection in two repeat transplant recipients. Clin Transpl. 2009. 23:479–83.

7). Chung BH., Hong YA., Sun IO., Piao SG., Kim JI., Moon IS, et al. Determination of rituximab dose according to immunologic risk in ABO-incompatible kidney transplantation. Ren Fail. 2012. 34:974–9.

8). Tobian AA., Shirey RS., Montgomery RA., Tisch DJ., Ness PM., King KE. Therapeutic plasma exchange reduces ABO titers to permit ABO-incompatible renal transplantation. Transfusion. 2009. 49:1248–54.

9). 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. 91:1218–26.

10). Kim M., Martin ST., Townsend KR., Gabardi S. Antibody-mediated rejection in kidney transplantation: a review of pathophysiology, diagnosis, and treatment options. Pharmacotherapy. 2014. 34:733–44.

11). Roberts DM., Jiang SH., Chadban SJ. The treatment of acute antibody-mediated rejection in kidney transplant recipients: a systematic review. Transplantation. 2012. 94:775–83.

12). Bonomini V., Vangelista A., Frasca GM., Di Felice A., Liviano D'Arcangelo G. Effects of plasmapheresis in renal transplant rejection. A controlled study. Trans Am Soc Artif Intern Organs. 1985. 31:698–703.

13). Allen NH., Dyer P., Geoghegan T., Harris K., Lee HA., Slapak M. Plasma exchange in acute renal allograft rejection. A controlled trial. Transplantation. 1983. 35:425–8.

14). Kirubakaran MG., Disney AP., Norman J., Pugsley DJ., Mathew TH. A controlled trial of plasmapheresis in the treatment of renal allograft rejection. Transplantation. 1981. 32:164–5.

15). Blake P., Sutton D., Cardella CJ. Plasma exchange in acute renal transplant rejection. Prog Clin Biol Res. 1990. 337:249–52.

16). Sberro-Soussan R., Zuber J., Suberbielle-Boissel C., Candon S., Martinez F., Snanoudj R, et al. Bortezomib as the sole post-renal transplantation desensitization agent does not decrease donor-specific anti-HLA antibodies. Am J Transplant. 2010. 10:681–6.

17). Philogene MC., Sikorski P., Montgomery RA., Leffell MS., Zachary AA. Differential effect of bortezomib on HLA class I and class II antibody. Transplantation. 2014. 98:660–5.

Fig. 1.

Serum creatinine changes after bortezomib treatment of the six patients who recovered. Serum creatinine levels began to decrease within 2 weeks of bortezomib treatment, and recovery was achieved within 2 months.

Table 1.

Preoperative patient characteristics

Case no.	Sex (age in yr)	Donor (age in yr)	Previous transplant history	ABO-I	HLA MN	PRA (Class I/II)	DSA		XM	RTX	Induct	PP
Case no.	Sex (age in yr)	Donor (age in yr)	Previous transplant history	ABO-I	HLA MN	PRA (Class I/II)	Initial	Pre-KT^a	XM	RTX	Induct	PP
1	F (43)	Spouse (48)	0	No	6	0/0	Neg	NA	Neg	No	BSX	0
2	M (38)	Deceased (45)	2	No	5	0/25	NA	B54 9827	Neg	No	ATG	0
3	F (46)	Son (19)	0	No	3	16/0	Neg	Neg	T, B CDC	1	BSX	9
4	F (32)	Spouse (37)	0	No	5	0/54	DR9 8121	DR9 3472	B	1	BSX	5
									FC
5	F (39)	Spouse (40)	0	1 (1:32)	5	16/60	A2 8578	A2 2671	T, B	1	BSX	10
									FC
6	F (47)	Daughter (29)	0	No	2	83/20	B51 3997	NA	Neg	1	ATG	0
7	F (57)	Spouse (54)	1	No	6	91/100	DR11 16371	DR11 3346	T, B	1	BSX	13
							DR14 14486	DR14 3781	FC
8	F (27)	Mother (52)	0	No	1	0/0	Neg	Neg	Neg	No	BSX	0

Abbreviations: ABO-I, ABO incompatibility; HLA MN, human leukocyte antigen mismatch number; PRA, panel-reactive antibody; DSA, donor-specific antibody; KT, kidney transplantation; XM, crossmatching; RTX, rituximab; PP, plasmapheresis; Neg, negative; NA, not assessed; BSX, basiliximab; ATG, anti-thymocyte globulin; T, T-cell; B, B-cell; CDC, complement-dependent cytotoxicity; FC, flowcytometry.

^a Last DSA before kidney transplantation.

Table 2.

Changes in donor-specific antibody levels during the peri-transplantation period

Case no.	Initial	Pre-KT^a	Pre-rejection^b	Rejection (pre-bortezomib^c)	Post-bortezomib^d	Follow-up
1	Neg	NA	NA	DR8 15741	DR8 3066	Neg (3, 6 mo)
2	NA	B54 9827	NA	B54 13333	B54 11089	NA
3	Neg	Neg	Neg	Neg	Neg	NA
4	DR9 8121	DR9 3472	Neg	DR9 15336	DR9 16440	DR9 13371 (7 mo)
5	A2 8578	A2 2671	A2 1996	A2 4876	Neg	Neg (2, 8, 11 mo)
6	B51 3997	NA	Neg	B51 1901	Neg	NA
7	DR11 16371	DR11 3346	Neg	Neg	Neg	NA
	DR14 14486	DR14 3781
8	Neg	Neg	Neg	Neg	Neg	NA

Abbreviations: KT, kidney transplantation; Neg, negative; NA, not assessed.

^a Last donor-specific antibody (DSA) before kidney transplantation;

^b Last DSA before rejection;

^c Last DSA before initiating bortezomib treatment;

^d Follow-up DSA after bortezomib treatment.

Table 3.

Treatments for transplant recipients exhibiting antibody-mediated rejection

Case no.	Rejection (POD)	Initial therapy	Bortezomib (POD)	Post-transplant plasmapheresis			HD start (POD)	HD end (POD)	Bx. (POD)
Case no.	Rejection (POD)	Initial therapy	Bortezomib (POD)	POD	Pre-bortezomib^a	Post-bortezomib^b	HD start (POD)	HD end (POD)	Bx. (POD)
1	4	Steroid pulse	19	9	5	7	6	28	8
		ATG
		Plasmapheresis
2	8	Steroid pulse	21	9	6	7	10	Maintain	8
		Plasmapheresis
3	6	Steroid pulse	12	8	2	8	-	-	10
		Plasmapheresis
4	4	Steroid pulse	10	4	2	1	7	Maintain	8
		Plasmapheresis
5	3	ATG	11	3	3	10	5	7	4
		Plasmapheresis
6	4	Steroid pulse	22	4	7	4	-	-	6
		Plasmapheresis
7	2	Steroid pulse	6	2	2	4	4	17	5
		Plasmapheresis
8	3	Steroid pulse	13	7	2	6	7	17	4
		ATG
		Plasmapheresis

Abbreviations: POD, postoperative day; HD, hemodialysis; Bx., graft biopsy; ATG, anti-thymocyte globulin.

^a Number of post-transplant plasmapheresis before initiating bortezomib treatment;

^b Number of plasmapheresis after first dose of bortezomib.

TOOLS

Similar articles