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The beneficial effects of FK 506 on living-related renal transplantation in presensitized recipients
The Beneficial Effects of FK 506 on Living-Related Renal Transplantation in Presensitized Recipients S. Miura, H. Okazaki, T. Sato, N. Amada, Y. Ohashi, and E. Hashizume
I
T HAS been recognized that recipient lymphocytotoxic antibodies directed to organ donor lymphocytes are frequently associated with hyperacute rejection. Therefore, for many years it has been standard practice to perform a crossmatch test against donor lymphocytes before transplantation.1,2 We previously reported that double-filtration plasmapheresis (DFPP) was effective in removing preformed antibodies and led to encouraging results in presensitized patients.3,4 However, with cyclosporine A (CyA), the graft survival rate was lower in presensitized patients than in sero-negative patients. From May 1996, FK 506 (tacrolimus, Prograf) has been commercially available for renal transplantation in Japan. In this study, we analyzed the effects of FK 506 on the clinical course of transplantation in presensitized recipients. PATIENTS AND METHODS The study was based on the data of 167 patients who received living-related or unrelated renal transplantation 4 weeks after donor-specific blood transfusion (DST) between June 1989 and June 1998. All patients were either HLA haploidentical or a totally mismatched pair (Table 1).
Crossmatch Test
Serum samples taken before and after DFPP treatment were tested for cytotoxic antibodies to donor lymphocytes. Table 1. Patient Characteristics
Number of patients Mean age (years) Female/Male HLA 1 Haplo mismatch 2 Haplo mismatch Unrelated Crossmatch Crossmatch(⫺) Bc(⫹); after DST Bc(⫹); before DST Tw(⫹) &/or Bw(⫹)
CyA
FK 506
124 33.8 (⫾11.7) 37/87
43 45.6 (⫾14.5) 14/30
117 2 5
31 6 6
65 19 20 20
28 2 7 6
Numbers in parentheses are mean ⫾ SD.
Fig 1.
Graft survival of recipients with CyA.
Cytotoxic antibodies against prospective donors were detected by standard or antiglobulin antibody-augmented crossmatch testing. Antibodies were classified by treatment of sera with dithiothreitol. Cytotoxic antibodies were positive in 74 patients before transplantation. The patients whose B-warm and T-warm antibodies were positive were observed with DFPP treatment until their cytotoxic antibodies became negative. The crossmatch negative or B-cold positive patients were transplanted without preoperative treatment. With CyA, the patients whose B-cold antibodies became positive after DST (Bc-aft) have had excellent graft outcome compared with those whose B-cold antibodies were positive before DST (Bc-bef) (Fig 1, 5-year graft survival; 100% in Bc-aft vs 77.9% in Bc-bef: P ⬍ .05). Considering this result, patients were divided into two groups as follows: a high-risk group (all of T-warm or B-warm positive and Bc-bef) and a low-risk group (crossmatch negative and Bc-aft). The patients did not differ in sex, number of HLAmismatches, and the rate of serological high-risk patients between the CyA- and FK 506-treated group (Table 1). 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, 981-8501, Japan.
© 1999 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/99/$–see front matter PII S0041-1345(99)00233-X
Transplantation Proceedings, 31, 1973–1975 (1999)
1973
1974
MIURA, OKAZAKI, SATO ET AL
Fig 3. Cumulative percentage of first acute rejection (KaplanMeier estimates). Fig 2.
Graft survival of recipients (Kaplan-Meier estimates).
As an initial immunosuppressive regimen, either FK 506 (0.3 mg/kg per day) or CyA (6 mg/kg per day) was given to the patients, combined with deoxyspergualin (DSG) (5 mg/kg), prednisolone (1 mg/kg), and antilymphocyte globulin. The DSG was switched to azathioprine (Az) 7 days after transplantation. Graft survival and the incidence of rejection episodes were evaluated in the two immunosuppressive groups. RESULTS
In the high-risk group, 1-year graft survival rates were 92.4% in CyA-treated patients and 100% in FK 506-treated patients. In the low-risk group, 1-year graft survival rates were 100% in both CyA-treated patients and in FK 506treated patients (Fig 2). In the high-risk group, the incidence of accelerated or acute rejection tended to be higher in CyA-treated patients than in FK 506-treated patients (Table 2, accelerated rejection; 4/39 (10.3%) in CyA-treated patients, 0/13 (0%) in FK 506-treated patients, acute rejection; 17/39 (43.6%) in CyA-treated patients, 2/13 (15.9%) in FK 506-treated patients). In the low-risk group, there was no difference in the incidence of accelerated or acute rejection between the two groups. In the high-risk group, the cumulative percentage of the first acute rejection was significantly lower in FK 506treated patients compared with CyA-treated patients (Fig 1). In the low-risk group, there was no significant difference in the cumulative percentage of the first acute
rejection between FK 506-treated patients and CyA-treated recipients. DISCUSSION
It has been reported that B-cold positive patients have excellent graft outcome.5 However, our results showed that the patients whose B-cold antibodies were positive before DST have had poor graft survival and almost the same result as B-warm or T-warm positive patients. In this study, we defined the patients whose B-cold antibodies were positive before DST as the high-risk group as well as T- or B-warm positive patients. In the high-risk group, the cumulative percentage of the first acute rejection in FK 506-treated patients was significantly lower compared with CyA-treated patients. Acute rejection has previously been shown to be closely correlated with the development of chronic allograft rejection and late graft loss.6,7 This data might indicate that FK 506 therapy might be associated with a prolongation of renal allograft survival in the serological high-risk patients, when compared with CyA. As the efficacy of FK 506 against human B-cell activation is supported by other reports, it is suggested that FK 506 might be a suitable immunosuppressant for serological high-risk patient.8 –10 CONCLUSION 1. The patients whose B-cold antibodies became positive after DST have had excellent graft outcome. 2. A significant reduction in the incidence of acute rejection in the serological high-risk patients was obtained with FK 506-based therapy.
Table 2. Clinical Course of Recipients
CyA Low risk High risk FK 506 Low risk High risk * P ⫽ .064.
No. of Patients
Accelerated Rejection
Severe Acute Rejection (⌬SCr ⬎ 1.0)
Acute Rejection (3 months)
Rejection Free (1 year)
85 39
5 (5.9%) 4 (10.3%)
5 (5.9%) 4 (10.3%)
25 (29.4%) 17 (43.6%)
57.8% 41.0%*
30 13
2 (6.7%) 0 (0%)
0 (0%) 0 (0%)
6 (20.0%) 2 (15.9%)
68.4% 72.7%*
BENEFICIAL EFFECTS OF FK 506
REFERENCES 1. Patel R, Terasaki PI: N Engl J Med 280:735, 1969 2. Morris PJ, Ting A, Oliver DO, et al: Lancet 1:1288, 1977 3. Miura S, Okazaki H, Sato T, et al: Transplant Proc 27:1040, 1995 4. Miura S, Okazaki H, Sato T, et al: Transplant Proc 29:350, 1997 5. Iwaki Y, Terasaki PI, Park MS, et al: Lancet 1:1228, 1978
1975 6. Almond PS, Matas A, Gillingham K, et al: Transplantation 55:752, 1993 7. Mayer AD, Dmitrewski J, Squifflet JP, et al: Transplantation 64:436, 1997 8. Morikawa K, Oseko F, Morikawa S: Transplantation 54:1025, 1992 9. Suzuki N, Sakane T, Tsunematsu T: Clin Exp Immunol 79(2):240, 1990 10. Lyne JC, Vivas CA, Shapiro R, et al: Transplant Proc 29:312, 1997
I
T HAS been recognized that recipient lymphocytotoxic antibodies directed to organ donor lymphocytes are frequently associated with hyperacute rejection. Therefore, for many years it has been standard practice to perform a crossmatch test against donor lymphocytes before transplantation.1,2 We previously reported that double-filtration plasmapheresis (DFPP) was effective in removing preformed antibodies and led to encouraging results in presensitized patients.3,4 However, with cyclosporine A (CyA), the graft survival rate was lower in presensitized patients than in sero-negative patients. From May 1996, FK 506 (tacrolimus, Prograf) has been commercially available for renal transplantation in Japan. In this study, we analyzed the effects of FK 506 on the clinical course of transplantation in presensitized recipients. PATIENTS AND METHODS The study was based on the data of 167 patients who received living-related or unrelated renal transplantation 4 weeks after donor-specific blood transfusion (DST) between June 1989 and June 1998. All patients were either HLA haploidentical or a totally mismatched pair (Table 1).
Crossmatch Test
Serum samples taken before and after DFPP treatment were tested for cytotoxic antibodies to donor lymphocytes. Table 1. Patient Characteristics
Number of patients Mean age (years) Female/Male HLA 1 Haplo mismatch 2 Haplo mismatch Unrelated Crossmatch Crossmatch(⫺) Bc(⫹); after DST Bc(⫹); before DST Tw(⫹) &/or Bw(⫹)
CyA
FK 506
124 33.8 (⫾11.7) 37/87
43 45.6 (⫾14.5) 14/30
117 2 5
31 6 6
65 19 20 20
28 2 7 6
Numbers in parentheses are mean ⫾ SD.
Fig 1.
Graft survival of recipients with CyA.
Cytotoxic antibodies against prospective donors were detected by standard or antiglobulin antibody-augmented crossmatch testing. Antibodies were classified by treatment of sera with dithiothreitol. Cytotoxic antibodies were positive in 74 patients before transplantation. The patients whose B-warm and T-warm antibodies were positive were observed with DFPP treatment until their cytotoxic antibodies became negative. The crossmatch negative or B-cold positive patients were transplanted without preoperative treatment. With CyA, the patients whose B-cold antibodies became positive after DST (Bc-aft) have had excellent graft outcome compared with those whose B-cold antibodies were positive before DST (Bc-bef) (Fig 1, 5-year graft survival; 100% in Bc-aft vs 77.9% in Bc-bef: P ⬍ .05). Considering this result, patients were divided into two groups as follows: a high-risk group (all of T-warm or B-warm positive and Bc-bef) and a low-risk group (crossmatch negative and Bc-aft). The patients did not differ in sex, number of HLAmismatches, and the rate of serological high-risk patients between the CyA- and FK 506-treated group (Table 1). 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, 981-8501, Japan.
© 1999 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/99/$–see front matter PII S0041-1345(99)00233-X
Transplantation Proceedings, 31, 1973–1975 (1999)
1973
1974
MIURA, OKAZAKI, SATO ET AL
Fig 3. Cumulative percentage of first acute rejection (KaplanMeier estimates). Fig 2.
Graft survival of recipients (Kaplan-Meier estimates).
As an initial immunosuppressive regimen, either FK 506 (0.3 mg/kg per day) or CyA (6 mg/kg per day) was given to the patients, combined with deoxyspergualin (DSG) (5 mg/kg), prednisolone (1 mg/kg), and antilymphocyte globulin. The DSG was switched to azathioprine (Az) 7 days after transplantation. Graft survival and the incidence of rejection episodes were evaluated in the two immunosuppressive groups. RESULTS
In the high-risk group, 1-year graft survival rates were 92.4% in CyA-treated patients and 100% in FK 506-treated patients. In the low-risk group, 1-year graft survival rates were 100% in both CyA-treated patients and in FK 506treated patients (Fig 2). In the high-risk group, the incidence of accelerated or acute rejection tended to be higher in CyA-treated patients than in FK 506-treated patients (Table 2, accelerated rejection; 4/39 (10.3%) in CyA-treated patients, 0/13 (0%) in FK 506-treated patients, acute rejection; 17/39 (43.6%) in CyA-treated patients, 2/13 (15.9%) in FK 506-treated patients). In the low-risk group, there was no difference in the incidence of accelerated or acute rejection between the two groups. In the high-risk group, the cumulative percentage of the first acute rejection was significantly lower in FK 506treated patients compared with CyA-treated patients (Fig 1). In the low-risk group, there was no significant difference in the cumulative percentage of the first acute
rejection between FK 506-treated patients and CyA-treated recipients. DISCUSSION
It has been reported that B-cold positive patients have excellent graft outcome.5 However, our results showed that the patients whose B-cold antibodies were positive before DST have had poor graft survival and almost the same result as B-warm or T-warm positive patients. In this study, we defined the patients whose B-cold antibodies were positive before DST as the high-risk group as well as T- or B-warm positive patients. In the high-risk group, the cumulative percentage of the first acute rejection in FK 506-treated patients was significantly lower compared with CyA-treated patients. Acute rejection has previously been shown to be closely correlated with the development of chronic allograft rejection and late graft loss.6,7 This data might indicate that FK 506 therapy might be associated with a prolongation of renal allograft survival in the serological high-risk patients, when compared with CyA. As the efficacy of FK 506 against human B-cell activation is supported by other reports, it is suggested that FK 506 might be a suitable immunosuppressant for serological high-risk patient.8 –10 CONCLUSION 1. The patients whose B-cold antibodies became positive after DST have had excellent graft outcome. 2. A significant reduction in the incidence of acute rejection in the serological high-risk patients was obtained with FK 506-based therapy.
Table 2. Clinical Course of Recipients
CyA Low risk High risk FK 506 Low risk High risk * P ⫽ .064.
No. of Patients
Accelerated Rejection
Severe Acute Rejection (⌬SCr ⬎ 1.0)
Acute Rejection (3 months)
Rejection Free (1 year)
85 39
5 (5.9%) 4 (10.3%)
5 (5.9%) 4 (10.3%)
25 (29.4%) 17 (43.6%)
57.8% 41.0%*
30 13
2 (6.7%) 0 (0%)
0 (0%) 0 (0%)
6 (20.0%) 2 (15.9%)
68.4% 72.7%*
BENEFICIAL EFFECTS OF FK 506
REFERENCES 1. Patel R, Terasaki PI: N Engl J Med 280:735, 1969 2. Morris PJ, Ting A, Oliver DO, et al: Lancet 1:1288, 1977 3. Miura S, Okazaki H, Sato T, et al: Transplant Proc 27:1040, 1995 4. Miura S, Okazaki H, Sato T, et al: Transplant Proc 29:350, 1997 5. Iwaki Y, Terasaki PI, Park MS, et al: Lancet 1:1228, 1978
1975 6. Almond PS, Matas A, Gillingham K, et al: Transplantation 55:752, 1993 7. Mayer AD, Dmitrewski J, Squifflet JP, et al: Transplantation 64:436, 1997 8. Morikawa K, Oseko F, Morikawa S: Transplantation 54:1025, 1992 9. Suzuki N, Sakane T, Tsunematsu T: Clin Exp Immunol 79(2):240, 1990 10. Lyne JC, Vivas CA, Shapiro R, et al: Transplant Proc 29:312, 1997