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Effect of Tacrolimus on the Outcome of Renal Transplantation With Donor-Specific Blood Transfusion
PRIMARY USE OF TACROLIMUS
Effect of Tacrolimus on the Outcome of Renal Transplantation With Donor-Specific Blood Transfusion S. Miura, H. Okazaki, T. Sato, N. Amada, and Y. Ohashi
D
ONOR-specific blood transfusion (DST) has been accepted as one of the effective ways for inducing specific immunologic unresponsiveness. We have reported that the 5-year graft survival rate in the DST-treated patients was 89.4% under combined immunosuppression of cyclosporine (CyA) and deoxyspergualin (DSG).1 Moreover, microchimerism was induced in the peripheral blood of DST-treated patients.2 However, severe accelerated rejection sometimes occurred within 1 week after transplantation. Since May 1996, FK 506 (tacrolimus, Prograf) has been commercially available for renal transplantation in Japan. In this study, the immunosuppressive efficacy of FK 506 was examined in our DST protocol and compared to that of CyA. PATIENTS AND METHODS The study was based on the data of 46 patients who received living-related or unrelated renal transplantation 4 weeks after DST between July 1994 and October 1997. All of them were either HLA haploidentical or a totally mismatched pair. Two sensitized patients by DST were excluded in this study. As an initial immunosuppressive regimen, FK 506 0.3 mg/kg (FK 506 group: n 5 23) or CyA 6 mg/kg (CyA group: n 5 21) was given to the patients combined with DSG (5 mg/kg), prednisolone Table 1. Patient Details
No. of patients Mean age (y) Female/male Donor age (y) HLA 1 haplo mismatch 2 haplo mismatch Unrelated Mean observation time (mo)
CyA
FK 506
21 35.5 6 2.6 9/12 50.1 6 2.6
23 37.0 6 2.6 7/16 53.3 6 2.3
16 2 2 23.2 6 2.0
15 1 4 11.1 6 1.0
Note: Numbers in parentheses are M 6 SE.
Table 2.
Clinical Courses of the Recipients
No. of Patients Accelerated rejection Acute rejection Severe accelerated or acute rejection (serum creatinine value .1.0) Rejection free during the first year
FK 506 (%)
CyA (%)
22* 2 (9.1) 2 (9.1) 0 (0)
21 2 (9.5) 5 (23.8) (P 5 .19) 3 (14.3) (P 5 .11)
18 (78.3)12 (57.1) (P 5 .08)
* One patient in the FK 506 group was excluded because FK 506 was converted to CyA in order to treat nephrotoxicity.
(1 mg/kg), and antilymphocyte globulin. DSG was switched to azathioprine (Az) 7 days after transplantation. The two groups did not differ in age, sex, number of HLA mismatches, or donor age (Table 1). The mean observation time per patient was 11.1 (61.0) months in the FK 506 group and 23.2 (62.0) months in the CyA group. One patient in the FK 506 group was excluded because FK 506 was converted to CyA in order to treat nephrotoxicity. Patient and graft survival rates and the incidence of rejection episodes were evaluated in the two groups.
RESULTS
One-year patient and graft survival rates were 100% in both groups. There was no difference in the incidence of accelerated or acute rejection between the two groups (accelerated rejection: 2 of 22 in the FK 506 group, 2 of 21 in the CyA group; acute rejection: 2 of 22 in the FK 506 group, 5 of 21 in the CyA group; Table 2). As shown in Fig 1, accelerated or acute rejection tended to be mild in the FK 506 group compared to the CyA group (rejection episodes in which serum creatinine level was elevated more than 1.0 From the Department of Surgery, Sendai Shakaihoken Hospital, Sendai, Japan. Address reprint requests to Dr Shunji Miura, Department of Surgery, Sendai Shakaihoken Hospital, 3-16-1, Tsutsumimachi, Aobaku, Sendai, 981, Japan.
0041-1345/98/$19.00 PII S0041-1345(98)00214-0
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
1212
Transplantation Proceedings, 30, 1212–1213 (1998)
ACCELERATED REJECTION
1213
potent pharmacologic and biologic manipulations. Therefore, we have continued to use our DST protocol in living donor transplantation, and obtained 98.7% and 89.4% 1 and 5-year graft survival, respectively, by the initial immunosuppression with CyA, DSG, prednisolone, and ALG. The most serious problem associated with DST is sensitization of recipients. In 81% of these cases, the antidonor antibody could be removed successfully with double filtration plasmapheresis.3 However, even in seronegative patients, severe accelerated rejection was occasionally seen within 1 week after transplantation, which was probably induced by nondetectable antibodies. Recently, we have introduced FK 506 in living-related or unrelated renal transplantation treated with DST. Though the number of patients was not enough to show a statistical difference, accelerated or acute rejection tended to be mild in the FK 506 group and the number of rejection episodes during the first year tended to be less. Other studies have reported a higher incidence of tremor, diarrhea, hyperglycemia, and angina pectoris in the FK 506 group.4 However, the incidence of serious side effects seems to be similar between the two groups. As the efficacy of FK 506 against accelerated rejection was supported by other reports, it was suggested that FK 506 might suppress antibody-mediated rejection and be a suitable immunosuppressant for DST-treated recipients.5,6 CONCLUSIONS Fig. 1
mg/dL: FK 506 group, 0/22; CyA group; 3/21: P 5 0.11). The rate of 1-year graft survival without rejection episode was 18/22 in the FK 506 group and 12 of 21 in the CyA group (P 5 .08). Nephrotoxicity and infectious diseases were similar between the two groups (Nephrotoxicity: 2 of 22 in the FK 506 group, 2 of 21 in the CyA group; infectious disease; 14 of 22 in the FK 506 group, 12 of 21 in the CyA group). Posttransplant diabetes mellitus tended to be more common in the FK 506 group compared to the CyA group (5 of 22 in the FK 506 group, 2 of 21 in the CyA group: P 5 .23). DISCUSSION
As we previously reported, we believe that improvement in graft survival could be achieved by the combined use of
In DST-treated recipients, there was no significant difference in the short-term outcome of renal transplantation between the CyA and FK 506 groups. However, FK 506 seems to be more effective than CyA in preventing severe accelerated or acute rejection. REFERENCES 1. Okazaki H, Sato T, Miura S, et al: Transplant Proc 29:200, 1997 2. Sakurada M, Okazaki H, Sato T, et al: Transplant Proc 29:1187, 1997 3. Miura S, Okazaki H, Sato T, et al: Transplant Proc 29:350, 1997 4. Mayer AD, Dmitrewski J, Squifflet JP, et al: Transplantation 64:436, 1997 5. Woodle ES, Newell KA, Haas M, et al: Clin Transplant 11:251, 1997 6. Lyne JC, Vivas CA, Shapiro R, et al: Transplant Proc 29:312, 1997
Effect of Tacrolimus on the Outcome of Renal Transplantation With Donor-Specific Blood Transfusion S. Miura, H. Okazaki, T. Sato, N. Amada, and Y. Ohashi
D
ONOR-specific blood transfusion (DST) has been accepted as one of the effective ways for inducing specific immunologic unresponsiveness. We have reported that the 5-year graft survival rate in the DST-treated patients was 89.4% under combined immunosuppression of cyclosporine (CyA) and deoxyspergualin (DSG).1 Moreover, microchimerism was induced in the peripheral blood of DST-treated patients.2 However, severe accelerated rejection sometimes occurred within 1 week after transplantation. Since May 1996, FK 506 (tacrolimus, Prograf) has been commercially available for renal transplantation in Japan. In this study, the immunosuppressive efficacy of FK 506 was examined in our DST protocol and compared to that of CyA. PATIENTS AND METHODS The study was based on the data of 46 patients who received living-related or unrelated renal transplantation 4 weeks after DST between July 1994 and October 1997. All of them were either HLA haploidentical or a totally mismatched pair. Two sensitized patients by DST were excluded in this study. As an initial immunosuppressive regimen, FK 506 0.3 mg/kg (FK 506 group: n 5 23) or CyA 6 mg/kg (CyA group: n 5 21) was given to the patients combined with DSG (5 mg/kg), prednisolone Table 1. Patient Details
No. of patients Mean age (y) Female/male Donor age (y) HLA 1 haplo mismatch 2 haplo mismatch Unrelated Mean observation time (mo)
CyA
FK 506
21 35.5 6 2.6 9/12 50.1 6 2.6
23 37.0 6 2.6 7/16 53.3 6 2.3
16 2 2 23.2 6 2.0
15 1 4 11.1 6 1.0
Note: Numbers in parentheses are M 6 SE.
Table 2.
Clinical Courses of the Recipients
No. of Patients Accelerated rejection Acute rejection Severe accelerated or acute rejection (serum creatinine value .1.0) Rejection free during the first year
FK 506 (%)
CyA (%)
22* 2 (9.1) 2 (9.1) 0 (0)
21 2 (9.5) 5 (23.8) (P 5 .19) 3 (14.3) (P 5 .11)
18 (78.3)12 (57.1) (P 5 .08)
* One patient in the FK 506 group was excluded because FK 506 was converted to CyA in order to treat nephrotoxicity.
(1 mg/kg), and antilymphocyte globulin. DSG was switched to azathioprine (Az) 7 days after transplantation. The two groups did not differ in age, sex, number of HLA mismatches, or donor age (Table 1). The mean observation time per patient was 11.1 (61.0) months in the FK 506 group and 23.2 (62.0) months in the CyA group. One patient in the FK 506 group was excluded because FK 506 was converted to CyA in order to treat nephrotoxicity. Patient and graft survival rates and the incidence of rejection episodes were evaluated in the two groups.
RESULTS
One-year patient and graft survival rates were 100% in both groups. There was no difference in the incidence of accelerated or acute rejection between the two groups (accelerated rejection: 2 of 22 in the FK 506 group, 2 of 21 in the CyA group; acute rejection: 2 of 22 in the FK 506 group, 5 of 21 in the CyA group; Table 2). As shown in Fig 1, accelerated or acute rejection tended to be mild in the FK 506 group compared to the CyA group (rejection episodes in which serum creatinine level was elevated more than 1.0 From the Department of Surgery, Sendai Shakaihoken Hospital, Sendai, Japan. Address reprint requests to Dr Shunji Miura, Department of Surgery, Sendai Shakaihoken Hospital, 3-16-1, Tsutsumimachi, Aobaku, Sendai, 981, Japan.
0041-1345/98/$19.00 PII S0041-1345(98)00214-0
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
1212
Transplantation Proceedings, 30, 1212–1213 (1998)
ACCELERATED REJECTION
1213
potent pharmacologic and biologic manipulations. Therefore, we have continued to use our DST protocol in living donor transplantation, and obtained 98.7% and 89.4% 1 and 5-year graft survival, respectively, by the initial immunosuppression with CyA, DSG, prednisolone, and ALG. The most serious problem associated with DST is sensitization of recipients. In 81% of these cases, the antidonor antibody could be removed successfully with double filtration plasmapheresis.3 However, even in seronegative patients, severe accelerated rejection was occasionally seen within 1 week after transplantation, which was probably induced by nondetectable antibodies. Recently, we have introduced FK 506 in living-related or unrelated renal transplantation treated with DST. Though the number of patients was not enough to show a statistical difference, accelerated or acute rejection tended to be mild in the FK 506 group and the number of rejection episodes during the first year tended to be less. Other studies have reported a higher incidence of tremor, diarrhea, hyperglycemia, and angina pectoris in the FK 506 group.4 However, the incidence of serious side effects seems to be similar between the two groups. As the efficacy of FK 506 against accelerated rejection was supported by other reports, it was suggested that FK 506 might suppress antibody-mediated rejection and be a suitable immunosuppressant for DST-treated recipients.5,6 CONCLUSIONS Fig. 1
mg/dL: FK 506 group, 0/22; CyA group; 3/21: P 5 0.11). The rate of 1-year graft survival without rejection episode was 18/22 in the FK 506 group and 12 of 21 in the CyA group (P 5 .08). Nephrotoxicity and infectious diseases were similar between the two groups (Nephrotoxicity: 2 of 22 in the FK 506 group, 2 of 21 in the CyA group; infectious disease; 14 of 22 in the FK 506 group, 12 of 21 in the CyA group). Posttransplant diabetes mellitus tended to be more common in the FK 506 group compared to the CyA group (5 of 22 in the FK 506 group, 2 of 21 in the CyA group: P 5 .23). DISCUSSION
As we previously reported, we believe that improvement in graft survival could be achieved by the combined use of
In DST-treated recipients, there was no significant difference in the short-term outcome of renal transplantation between the CyA and FK 506 groups. However, FK 506 seems to be more effective than CyA in preventing severe accelerated or acute rejection. REFERENCES 1. Okazaki H, Sato T, Miura S, et al: Transplant Proc 29:200, 1997 2. Sakurada M, Okazaki H, Sato T, et al: Transplant Proc 29:1187, 1997 3. Miura S, Okazaki H, Sato T, et al: Transplant Proc 29:350, 1997 4. Mayer AD, Dmitrewski J, Squifflet JP, et al: Transplantation 64:436, 1997 5. Woodle ES, Newell KA, Haas M, et al: Clin Transplant 11:251, 1997 6. Lyne JC, Vivas CA, Shapiro R, et al: Transplant Proc 29:312, 1997