Living-donor Kidney Transplantation With Existing Anti-donor Specific Antibodies at a Japanese Single Center H. Ushigomea,*, S. Haradaa, M. Nakaoa, T. Nakamuraa, K. Koshinoa, T. Suzukib, T. Itoa, S. Noboria, and N. Yoshimuraa,b a
Department of Transplantation and Regenerative Surgery, Kyoto Prefectural University of Medicine, Kyoto City, Japan; and Department of Organ Interaction Research Medicine, Kyoto Prefectural University of Medicine, Kyoto City, Japan
b
ABSTRACT Improving the short-term outcome of kidney transplantation, the rejection induced by anti-donor specific antibody (DSA) has been the large complication. We analyzed 324 living-donor kidney transplant recipients (procedures performed between April 2003 and August 2014) to investigate the outcome of kidney transplant recipients with DSA. We divided them into four groups (anti-blood type antibody alone, group A [n ¼ 73]; antihuman lymphocyte antigen [HLA] antibody alone, group B [n ¼ 11]; both antibodies, group C [n ¼ 8]; and no DSA, group D [n ¼ 232]) and investigated the incidence of rejection and those histologic findings. Each case with DSA underwent some desensitization therapy before transplantation. There was no significant difference in graft survival (all cases: 100% at 1 year, group A: 97.6%, B: 95.9%, C: 100%, and at 5 years, group D: 96.1%). There were some significant differences in incidence of acute antibody-mediated rejection (AAMR) and chronic active antibody-mediated rejection (CAAMR) among four groups (group A: 4.1% and 2.7%, B: 18.2% and 9.1%, C: 12.5% and 12.5%, D: 0% and 0.9%, respectively). Each AAMR case was improved by ordinary desensitization therapy, but half of the CAAMR cases, diagnosed early after transplantation, had no effect of any therapy to result in graft failure. Our results suggested that even the case with DSA could be transplanted safely by some desensitization therapy. However, we should be cautious regarding recipients with DSA for the long term even if there is no histologic change early after transplantation because graft loss may occur due to CAAMR.
A
CCORDING to the recent development of some new methods such as flow cytometry crossmatch (FCXM) and flow cytometry panel-reactive antibody (Flow-PRA) to detect donor specific antibody (DSA) with higher sensitivity, the number of recipients with actual DSA by these methods has increased even if classical lymphocyte cytotoxicity tests were negative. Acute antibody-mediated rejection (AAMR) has been avoided beforehand by performing desensitization by the ABO blood type incompatible transplantation method. Consequently, the improvement of outcomes of kidney transplant recipients with DSA have been realized and contributed to increasing the number of donor candidates. However, as for chronic active antibody-mediated rejection (CAAMR), an adequate system for following up and an effective therapy has not been established yet. This study investigates the outcome of living-donor kidney transplant recipients with DSA. 0041-1345/15 http://dx.doi.org/10.1016/j.transproceed.2014.12.039
612
PATIENTS AND METHODS Patients Ninety-two (28.4%) of 324 living-donor kidney transplant recipients have had existing DSA in our institution from April 2003 to August 2014. We divided them into four groups (group A [anti-donor blood type antibody alone, n ¼ 73], group B [anti-donor human lymphocyte antigen [HLA] antibody alone, n ¼ 11], group C [both antibodies, n ¼ 8], and group D [no DSA, n ¼ 232]) and compared the incidences of rejection and the histologic findings among them.
Screening for DSA We have routinely surveilled anti-donor specific HLA antibodies of kidney transplant recipients by lymphocyte cytotoxicity test, FCXM, *Address correspondence to Hidetaka Ushigome, MD, PhD, Department of Transplantation and Regenerative Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto City, Japan 602-8566. E-mail: [email protected] ª 2015 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
Transplantation Proceedings, 47, 612e616 (2015)
LIVING-DONOR KIDNEY TRANSPLANTATION
613
Fig 1. Immunosuppressive protocol in kidney transplantation for the recipient with anti-donor specific antigen. Mycophenolate mofetil (MMF) and prednisolone are administrated for 14 days before transplantation. Rituximab is administrated on 14 days and 7 days before transplantation instead of splenectomy. Cyclosporine A or tacrolimus is administered for 5 days before transplantation. Their doses are adjusted according to the blood trough level. Basiliximab is administrated intravenously on the day and 4 days after transplantation. Double filtration plasmapheresis or plasma exchange is performed before transplantation 1e4 times corresponding with anti-donor antibodies titer. On day 1 after transplantation, MMF or mizoribine is administrated orally. Prednisolone is reduced gradually every week.
and Flow-PRA since April 2003. After confirmation of the existing antibody, we have used single antigen beads (SABs), such as Luminex antigen beads (LABs), screening to specify and quantify the target HLA. At Kyoto Prefectural University Hospital, mean fluorescence intensity (MFI) < 2000 quantified by LAB screening after the desensitization therapy has been suitable for kidney transplantation.
Statistical Analysis Statistical analysis was performed with one-way analysis of variance or with Kruskal-Wallis analysis of variance when assumptions of normality of the distribution or homogeneity of variances were not verified. Data values are reported as mean SD. Two-tailed values of P < .05 were considered to indicate statistical significance. All statistical analyses were performed using SPSS version 11.0J (SPSS Inc. Chicago, Ill, United States).
Immunosuppressants The immunosuppressive regimen was based on usual ABO blood type incompatible kidney transplantation at Kyoto Prefectural University Hospital [1,2]. The regimen of cyclosporine A (CsA) or tacrolimus (Tac), mycophenolate mofetil (MMF) or mizoribine (Mz) and prednisolone (PSL) with desensitization therapy is described in Fig 1. We perform the plasma exchange (PEX) before transplantation 1 to 4 times preoperatively corresponding with anti-donor antibodies titer and aim to decrease the anti-donor antibodies titer so as not to be detected by FCXM (2). Additionally, rituximab (RIT, 100 to 200 mg) is administrated at 14 days and 7 days before transplantation instead of splenectomy [2].
Histologic Diagnosis After transplantation we performed biopsies at least three times that involve routine protocol biopsies of 1 hour, 1 month, and 1 year after transplantation. Histologic findings were categorized according to the Banff 2003 meeting report [3] and Banff 2007 classification [4]. Analysis of paraffin-polyclonal antibody-immunohistochemistry techniques were used for C4d staining [5].
RESULTS Baseline Characteristics of Four Groups
Ninety-two living-donor kidney transplant recipients had DSA such as anti-blood type and anti-HLA antibody detected before transplantation. Table 1 shows the baseline characteristics of these 324 recipients that were divided to four groups. There were no significant differences in the recipient mean ages and dialysis periods among three groups. As for gender, females in groups B (91%) and C (100%) were significantly more than in groups A (38.4%) and group D (36.6%). The number of retransplantations in group B (27.3%) was significantly larger than that in groups A (1.4%) and D (1.1%). There was no significant difference in quantity of DSA such as anti-blood type antibody titers and MFI levels of anti-HLA antibody among three groups with DSA. Anti-blood type antibody titers were 175.6 394.6 in group A and 44.5 40.2 in group C. MFI levels of anti-HLA antibody were 4132.9 2777.3 in group B and
614
USHIGOME, HARADA, NAKAO ET AL Table 1. Baseline Characteristics of Living-donor Kidney Recipients With Anti-donor Specific Antibodies
Recipients Age (y, mean SD, range) Gender (female; %) Dialysis period (mo; mean SD) Retransplantation (%) Donor Age (y, mean SD, range) Gender (female; %) Patient: parent, child, sibling, spouse Quantity of DSA Anti-blood group antibody (titer; mean SD) Anti-HLA antibody (MFI; mean SD) Desensitization Dose of RIT (mg; mean SD) Frequency of PEX (mean SD) Immunodepression (with Bx þ PSL) CsA þ MZ (%) CsA þ MMF (%) Tac þ MZ (%) Tac þ MMF (%)
Group A (n ¼ 73)
Group B (n ¼ 11)
Group C (n ¼ 8)
Group D (n ¼ 232)
(Anti-blood Type Antibody)
(Anti-HLA Antibody)
(Both Antibodies)
(No DSA)
P
48.9 13.8, 9e69 28; 38.4 45.8 81.9 1.4
49.1 14.5, 17e63 43.6 9.6, 31e60 41.5 15.8, 4e73 NS 10; 90.9* 8; 100* 85; 36.6
Department of Transplantation and Regenerative Surgery, Kyoto Prefectural University of Medicine, Kyoto City, Japan; and Department of Organ Interaction Research Medicine, Kyoto Prefectural University of Medicine, Kyoto City, Japan
b
ABSTRACT Improving the short-term outcome of kidney transplantation, the rejection induced by anti-donor specific antibody (DSA) has been the large complication. We analyzed 324 living-donor kidney transplant recipients (procedures performed between April 2003 and August 2014) to investigate the outcome of kidney transplant recipients with DSA. We divided them into four groups (anti-blood type antibody alone, group A [n ¼ 73]; antihuman lymphocyte antigen [HLA] antibody alone, group B [n ¼ 11]; both antibodies, group C [n ¼ 8]; and no DSA, group D [n ¼ 232]) and investigated the incidence of rejection and those histologic findings. Each case with DSA underwent some desensitization therapy before transplantation. There was no significant difference in graft survival (all cases: 100% at 1 year, group A: 97.6%, B: 95.9%, C: 100%, and at 5 years, group D: 96.1%). There were some significant differences in incidence of acute antibody-mediated rejection (AAMR) and chronic active antibody-mediated rejection (CAAMR) among four groups (group A: 4.1% and 2.7%, B: 18.2% and 9.1%, C: 12.5% and 12.5%, D: 0% and 0.9%, respectively). Each AAMR case was improved by ordinary desensitization therapy, but half of the CAAMR cases, diagnosed early after transplantation, had no effect of any therapy to result in graft failure. Our results suggested that even the case with DSA could be transplanted safely by some desensitization therapy. However, we should be cautious regarding recipients with DSA for the long term even if there is no histologic change early after transplantation because graft loss may occur due to CAAMR.
A
CCORDING to the recent development of some new methods such as flow cytometry crossmatch (FCXM) and flow cytometry panel-reactive antibody (Flow-PRA) to detect donor specific antibody (DSA) with higher sensitivity, the number of recipients with actual DSA by these methods has increased even if classical lymphocyte cytotoxicity tests were negative. Acute antibody-mediated rejection (AAMR) has been avoided beforehand by performing desensitization by the ABO blood type incompatible transplantation method. Consequently, the improvement of outcomes of kidney transplant recipients with DSA have been realized and contributed to increasing the number of donor candidates. However, as for chronic active antibody-mediated rejection (CAAMR), an adequate system for following up and an effective therapy has not been established yet. This study investigates the outcome of living-donor kidney transplant recipients with DSA. 0041-1345/15 http://dx.doi.org/10.1016/j.transproceed.2014.12.039
612
PATIENTS AND METHODS Patients Ninety-two (28.4%) of 324 living-donor kidney transplant recipients have had existing DSA in our institution from April 2003 to August 2014. We divided them into four groups (group A [anti-donor blood type antibody alone, n ¼ 73], group B [anti-donor human lymphocyte antigen [HLA] antibody alone, n ¼ 11], group C [both antibodies, n ¼ 8], and group D [no DSA, n ¼ 232]) and compared the incidences of rejection and the histologic findings among them.
Screening for DSA We have routinely surveilled anti-donor specific HLA antibodies of kidney transplant recipients by lymphocyte cytotoxicity test, FCXM, *Address correspondence to Hidetaka Ushigome, MD, PhD, Department of Transplantation and Regenerative Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto City, Japan 602-8566. E-mail: [email protected] ª 2015 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
Transplantation Proceedings, 47, 612e616 (2015)
LIVING-DONOR KIDNEY TRANSPLANTATION
613
Fig 1. Immunosuppressive protocol in kidney transplantation for the recipient with anti-donor specific antigen. Mycophenolate mofetil (MMF) and prednisolone are administrated for 14 days before transplantation. Rituximab is administrated on 14 days and 7 days before transplantation instead of splenectomy. Cyclosporine A or tacrolimus is administered for 5 days before transplantation. Their doses are adjusted according to the blood trough level. Basiliximab is administrated intravenously on the day and 4 days after transplantation. Double filtration plasmapheresis or plasma exchange is performed before transplantation 1e4 times corresponding with anti-donor antibodies titer. On day 1 after transplantation, MMF or mizoribine is administrated orally. Prednisolone is reduced gradually every week.
and Flow-PRA since April 2003. After confirmation of the existing antibody, we have used single antigen beads (SABs), such as Luminex antigen beads (LABs), screening to specify and quantify the target HLA. At Kyoto Prefectural University Hospital, mean fluorescence intensity (MFI) < 2000 quantified by LAB screening after the desensitization therapy has been suitable for kidney transplantation.
Statistical Analysis Statistical analysis was performed with one-way analysis of variance or with Kruskal-Wallis analysis of variance when assumptions of normality of the distribution or homogeneity of variances were not verified. Data values are reported as mean SD. Two-tailed values of P < .05 were considered to indicate statistical significance. All statistical analyses were performed using SPSS version 11.0J (SPSS Inc. Chicago, Ill, United States).
Immunosuppressants The immunosuppressive regimen was based on usual ABO blood type incompatible kidney transplantation at Kyoto Prefectural University Hospital [1,2]. The regimen of cyclosporine A (CsA) or tacrolimus (Tac), mycophenolate mofetil (MMF) or mizoribine (Mz) and prednisolone (PSL) with desensitization therapy is described in Fig 1. We perform the plasma exchange (PEX) before transplantation 1 to 4 times preoperatively corresponding with anti-donor antibodies titer and aim to decrease the anti-donor antibodies titer so as not to be detected by FCXM (2). Additionally, rituximab (RIT, 100 to 200 mg) is administrated at 14 days and 7 days before transplantation instead of splenectomy [2].
Histologic Diagnosis After transplantation we performed biopsies at least three times that involve routine protocol biopsies of 1 hour, 1 month, and 1 year after transplantation. Histologic findings were categorized according to the Banff 2003 meeting report [3] and Banff 2007 classification [4]. Analysis of paraffin-polyclonal antibody-immunohistochemistry techniques were used for C4d staining [5].
RESULTS Baseline Characteristics of Four Groups
Ninety-two living-donor kidney transplant recipients had DSA such as anti-blood type and anti-HLA antibody detected before transplantation. Table 1 shows the baseline characteristics of these 324 recipients that were divided to four groups. There were no significant differences in the recipient mean ages and dialysis periods among three groups. As for gender, females in groups B (91%) and C (100%) were significantly more than in groups A (38.4%) and group D (36.6%). The number of retransplantations in group B (27.3%) was significantly larger than that in groups A (1.4%) and D (1.1%). There was no significant difference in quantity of DSA such as anti-blood type antibody titers and MFI levels of anti-HLA antibody among three groups with DSA. Anti-blood type antibody titers were 175.6 394.6 in group A and 44.5 40.2 in group C. MFI levels of anti-HLA antibody were 4132.9 2777.3 in group B and
614
USHIGOME, HARADA, NAKAO ET AL Table 1. Baseline Characteristics of Living-donor Kidney Recipients With Anti-donor Specific Antibodies
Recipients Age (y, mean SD, range) Gender (female; %) Dialysis period (mo; mean SD) Retransplantation (%) Donor Age (y, mean SD, range) Gender (female; %) Patient: parent, child, sibling, spouse Quantity of DSA Anti-blood group antibody (titer; mean SD) Anti-HLA antibody (MFI; mean SD) Desensitization Dose of RIT (mg; mean SD) Frequency of PEX (mean SD) Immunodepression (with Bx þ PSL) CsA þ MZ (%) CsA þ MMF (%) Tac þ MZ (%) Tac þ MMF (%)
Group A (n ¼ 73)
Group B (n ¼ 11)
Group C (n ¼ 8)
Group D (n ¼ 232)
(Anti-blood Type Antibody)
(Anti-HLA Antibody)
(Both Antibodies)
(No DSA)
P
48.9 13.8, 9e69 28; 38.4 45.8 81.9 1.4
49.1 14.5, 17e63 43.6 9.6, 31e60 41.5 15.8, 4e73 NS 10; 90.9* 8; 100* 85; 36.6
