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Japanese single-center experience of kidney transplantation under tacrolimus immunosuppression
Japanese Single-Center Experience of Kidney Transplantation Under Tacrolimus Immunosuppression K. Tanabe, T. Tokumoto, N. Ishikawa, T. Shimizu, H. Okuda, S. Ito, H. Shimmura, M. Inui, M. Harano, M. Manu, S. Koga, S. Ohtsubo, K. Suzuki, Y. Shiroyanagi, N. Goya, H. Nakazawa, T. Yagisawa, I. Nakajima, S. Fuchinoue, and H. Toma
T
ACROLIMUS is a potent immunosuppressive agent that was launched in Japan in April 1996 and has been used with encouraging short-term results in kidney transplantation.1–5 However, the optimal manner in which it should be used has not yet been established. One question has concerned the optimal concentration of tacrolimus trough levels not only to prevent acute rejection but also to prevent adverse effects, such as nephrotoxicity and cardiac events.5 In this study we not only reviewed the results of kidney transplantation under tacrolimus immunosuppression after its launching in Japan but also tried to find the optimal usage of tacrolimus. MATERIALS AND METHODS One hundred and thirty-three patients with end-stage renal failure underwent kidney transplantation under tacrolimus immunosuppression at our institute between April 19, 1996, and December 31, 1998. The mean age was 35 ⫾ 13 years (range, 1 to 68 years), with 85 men and 48 women. One hundred and fourteen were livingrelated renal transplantation and 19 were cadaveric transplantation. Seventeen patients were ABO-incompatible and 116 were ABO-compatible renal transplantation. In the induction phase, methylprednisolone, tacrolimus, and mizoribine or azathioprine were used for immunosuppression. An oral dose of tacrolimus, 0.15 mg/kg every 12 hours, was initially administered for 2 days before transplantation. After revascularization, 0.05 to 0.1 mg/kg per day of the drug was given intravenously for 1 to 2 consecutive days, followed by about 0.15 mg/kg orally every 12 hours. The tacrolimus dose was adjusted when rejection or adverse effects were observed. Methylprednisolone administration was started on the day of transplantation, at a dose of 125 to 500 mg/d, and reduced to a maintenance dose of 8 mg/d by the end of second month. All recipients were subdivided into two groups according to the target trough levels of tacrolimus. The oral dose in group 1 was adjusted to maintain an tacrolimus whole-blood trough level of 20 to 25 ng/mL whole blood by IMX for the first 2 weeks after transplantation, 20 ng/mL by 1 month, 15 to 20 ng/mL by 3 months, 10 ng/mL by 1 year, and 5 to 10 ng/mL thereafter. In group 2 we changed target trough levels in relatively lower concentration compared to those of group 1, with target trough levels of 15 ng/mL for first 2 weeks 10 to 15 ng/mL by 1 month, 10 ng/mL by 3 months, 5 to 10 ng/mL by 1 year, and 5 ng/mL chronically. Group 1 included 66 patients who underwent kidney transplantation between April 1996 and December 1997. Group 2 included 67 patients who underwent kidney transplantation in 1998. Recipient and donor
Table 1. Recipient/Donor Demographics No. of patients Sex (M/F) Recipient age (y) Duration of hemodialysis (mo) Donor source (LD/CD) ABO-compatibility (Com./Incomp.) Donor age (y) HLA-AB mismatch 0 1 2 3 4 HLA-DR mismatch 0 1 2
133 85/48 35 ⫾ 13 50 ⫾ 59 114/19 116/17 53 ⫾ 14 19 46 60 4 1 54 71 7
LD, living donor; CD, cadaveric donor.
demographics are shown in Table 1. Only the number of ABOincompatible transplantation was significantly different between the two groups.
RESULTS Patient and Graft Survival
Patient survival rates in both groups were almost identical, and no significant difference was noted (Fig 1). Group 2 showed significantly better graft survival than that of group 1 (groups 1 and 2, 97% vs 86% at 1 year, respectively, P ⫽ .027) (Fig 2). Tacrolimus Trough Levels
Tacrolimus trough levels were significantly higher in group 1 than in group 2 up to 3 months posttransplantation (Fig 3). From the Department of Urology, Tokyo Women’s Medical University, Tokyo, Japan. Address reprint requests to Kazunari Tanabe, MD, Section of Renal Transplantation/Renovascular Surgery, Department of Urology, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan.
0041-1345/00/$–see front matter PII S0041-1345(00)01410-X
© 2000 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
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Transplantation Proceedings, 32, 1696–1699 (2000)
KIDNEY TRANSPLANT AND TACROLIMUS
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Fig 1. Patient survival (KaplanMeier).
Causes of Death
Rejection
Two patients died with functioning graft during the observation period, and the causes of death were malignant lymphoma and cardiac failure in the early postoperative period.
Rejection was biopsy-proven in over 90% of cases and was treated initially with 500-mg bolus steroid pulse therapy. The overall rejection episodes occurred in 62 patients (47%). Although rejection episodes in group 1 occurred in 38 patients (58%), in group 2 only 24 patients (36%) experienced acute rejection. However, 8 of 38 patients who experienced rejection in group 1 had the rejection episodes during cyclosporine (CyA) treatment because 19 patients of group 1 converted from tacrolimus to CyA for tacrolimusrelated adverse effects. As a result, rate of acute rejection
Causes of Graft Loss
Among 133 patients, 12 grafts were lost during the observation period. Loss was due to acute rejection in 7 patients, followed by death with function in 2 patients, and chronic rejection, sepsis, and PTLD in 1 patient each.
Fig 2. Graft survival (KaplanMeier).
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TANABE, TOKUMOTO, ISHIKAWA ET AL
Fig 3. Tacrolimus trough levels.
during tacrolimus treatment in group 1 was almost the same, about 37% (Table 2). Complications and Adverse Effects
Table 3 is a summary of complications and adverse effects of tacrolimus. Overall nephrotoxicity occurred in 15% of all patients. Group 2 patients showed significantly lower incidence of nephrotoxicity (3%) than did group 1 patients (27%). Cardiac events, such as chest pain and palpitations, were not frequent in group 2 compared to group 1. Posttransplant diabetes mellitus (PTDM) was not so frequent in this series, which was about 8%, and only 1.5% of the patients required long-term insulin therapy, which is even slightly better than those of CyA-based immunosuppression. Conversion
Because of adverse effects, tacrolimus was converted to CyA in 20% of all recipients. Half of those recipients who had been converted to CyA-based immunosuppression reconverted to tacrolimus, mainly due to rejection. Two of eight patients who had been converted to CyA due to cardiac events were still on CyA treatment; however, six patients were reconverted to tacrolimus owing to acute rejection and recurrence of FSGS. Eleven patients were converted to CyA due to nephrotoxicity. Six of these 11 patients were reconverted to tacrolimus due to rejection or FSGS during CyA treatment. Table 2. Rejection Rates During Tacrolimus Treatment Incidence of Rejection
Overall Group 1 Group 2
(n ⫽ 66) (n ⫽ 67)
(4/96 –12/98) (4/96 –12/98) (1/98 –12/98)
62 (47%) 38 (58%) 24 (36%)
P⫽.019
DISCUSSION
The efficacy of tacrolimus as a primary immunosuppressive agent in renal transplant recipients has been reported in a number of clinical trials.1–5 Reasonable 1- and 3-year patient and graft survival rates of 99% and 97%, and 92% and 90%, respectively, have been achieved. However, there are still some problems, such as malabsorption, nephrotoxicity, PTDM, and cardiac events. Determination of optimal target trough levels of tacrolimus appears to play a key role in solving these problems. Although rejection episodes in group 1 occurred in 38 patients (58%), in group 2 only 24 patients (36%) experienced acute rejection (Table 1). However, 8 of 38 patients who experienced rejection in group 1 had the rejection episodes during CyA treatment, because 19 patients of group 1 converted from tacrolimus to CyA for tacrolimusrelated adverse effects. As a result, rate of acute rejection during tacrolimus treatment in group 1 was almost the same, which was about 37%. This means that high trough levels cause tacrolimus-related adverse effects and the patients were forced to convert to CyA, and eventually got rejection episodes and were forced to reconvert to tacroliTable 3. Complications and Adverse Effects of Tacrolimus Treatment Complication
Group 1 (n ⫽ 66)
Group 2 (n ⫽ 67)
Hypertension Hyperuricemia Nephrotoxicity Hyperlipidemia Posttransplant DM (long-term insulin dependent) CMV disease Cardiac events
19 (29%) 22 (33%) 18 (27%) 10 (15%) 5 (8%) (1) (1.5%) 7 (11%) 6 (9%)
22 (33%) 6 (9%) 2 (3%) 1 (1.5%) 5 (7.5%) (1) (1.5%) 3 (4.5%) 2 (3%)
P
.6132 .0006 .0007 .0042 .9803 .0271 .3027
KIDNEY TRANSPLANT AND TACROLIMUS
mus. From these results, we recommend the lower p.o. tacrolimus dosage and not to convert to CyA for tacrolimusrelated adverse effects. Tacrolimus-induced PTDM is an important adverse event, but is readily reversible with dosage reduction of tacrolimus. Only 1.5% of all patients in this series required long-term insulin therapy, which is the same as that of CyA-based immunosuppressed patients. Incidence of nephrotoxicity was also markedly reduced in group 2 by lowering target trough levels in early period of transplantation. In summary, many significant benefits are associated with tacrolimus-based immunosuppression in renal transplantation and, with increasing experience, the incidence of adverse events can be reduced. We believe that 15 ng/mL of tacrolimus trough level in the induction phase is the optimal concentration.
1699
CONCLUSIONS
Kidney transplantation under tacrolimus immunosuppression after launching in Japan offers an excellent outcome. We conclude that 15 ng/mL of tacrolimus trough level in induction phase seemed to be the optimal concentration.
REFERENCES 1. Starzl TE, Fung JJ, Jordan M, et al: JAMA 63:264, 1990 2. Shapiro R: Transplant Proc 29:45, 1997 3. Woodle ES, Thistlethwaite JR, Gordon JH, et al: Transplantation 62:594, 1996 4. Jordan ML, Shapiro R, Vivas CA, et al: Transplantation 57:860, 1994 5. Japanese FK506 Study Group: Transplant Proc 25:649, 1993
T
ACROLIMUS is a potent immunosuppressive agent that was launched in Japan in April 1996 and has been used with encouraging short-term results in kidney transplantation.1–5 However, the optimal manner in which it should be used has not yet been established. One question has concerned the optimal concentration of tacrolimus trough levels not only to prevent acute rejection but also to prevent adverse effects, such as nephrotoxicity and cardiac events.5 In this study we not only reviewed the results of kidney transplantation under tacrolimus immunosuppression after its launching in Japan but also tried to find the optimal usage of tacrolimus. MATERIALS AND METHODS One hundred and thirty-three patients with end-stage renal failure underwent kidney transplantation under tacrolimus immunosuppression at our institute between April 19, 1996, and December 31, 1998. The mean age was 35 ⫾ 13 years (range, 1 to 68 years), with 85 men and 48 women. One hundred and fourteen were livingrelated renal transplantation and 19 were cadaveric transplantation. Seventeen patients were ABO-incompatible and 116 were ABO-compatible renal transplantation. In the induction phase, methylprednisolone, tacrolimus, and mizoribine or azathioprine were used for immunosuppression. An oral dose of tacrolimus, 0.15 mg/kg every 12 hours, was initially administered for 2 days before transplantation. After revascularization, 0.05 to 0.1 mg/kg per day of the drug was given intravenously for 1 to 2 consecutive days, followed by about 0.15 mg/kg orally every 12 hours. The tacrolimus dose was adjusted when rejection or adverse effects were observed. Methylprednisolone administration was started on the day of transplantation, at a dose of 125 to 500 mg/d, and reduced to a maintenance dose of 8 mg/d by the end of second month. All recipients were subdivided into two groups according to the target trough levels of tacrolimus. The oral dose in group 1 was adjusted to maintain an tacrolimus whole-blood trough level of 20 to 25 ng/mL whole blood by IMX for the first 2 weeks after transplantation, 20 ng/mL by 1 month, 15 to 20 ng/mL by 3 months, 10 ng/mL by 1 year, and 5 to 10 ng/mL thereafter. In group 2 we changed target trough levels in relatively lower concentration compared to those of group 1, with target trough levels of 15 ng/mL for first 2 weeks 10 to 15 ng/mL by 1 month, 10 ng/mL by 3 months, 5 to 10 ng/mL by 1 year, and 5 ng/mL chronically. Group 1 included 66 patients who underwent kidney transplantation between April 1996 and December 1997. Group 2 included 67 patients who underwent kidney transplantation in 1998. Recipient and donor
Table 1. Recipient/Donor Demographics No. of patients Sex (M/F) Recipient age (y) Duration of hemodialysis (mo) Donor source (LD/CD) ABO-compatibility (Com./Incomp.) Donor age (y) HLA-AB mismatch 0 1 2 3 4 HLA-DR mismatch 0 1 2
133 85/48 35 ⫾ 13 50 ⫾ 59 114/19 116/17 53 ⫾ 14 19 46 60 4 1 54 71 7
LD, living donor; CD, cadaveric donor.
demographics are shown in Table 1. Only the number of ABOincompatible transplantation was significantly different between the two groups.
RESULTS Patient and Graft Survival
Patient survival rates in both groups were almost identical, and no significant difference was noted (Fig 1). Group 2 showed significantly better graft survival than that of group 1 (groups 1 and 2, 97% vs 86% at 1 year, respectively, P ⫽ .027) (Fig 2). Tacrolimus Trough Levels
Tacrolimus trough levels were significantly higher in group 1 than in group 2 up to 3 months posttransplantation (Fig 3). From the Department of Urology, Tokyo Women’s Medical University, Tokyo, Japan. Address reprint requests to Kazunari Tanabe, MD, Section of Renal Transplantation/Renovascular Surgery, Department of Urology, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan.
0041-1345/00/$–see front matter PII S0041-1345(00)01410-X
© 2000 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
1696
Transplantation Proceedings, 32, 1696–1699 (2000)
KIDNEY TRANSPLANT AND TACROLIMUS
1697
Fig 1. Patient survival (KaplanMeier).
Causes of Death
Rejection
Two patients died with functioning graft during the observation period, and the causes of death were malignant lymphoma and cardiac failure in the early postoperative period.
Rejection was biopsy-proven in over 90% of cases and was treated initially with 500-mg bolus steroid pulse therapy. The overall rejection episodes occurred in 62 patients (47%). Although rejection episodes in group 1 occurred in 38 patients (58%), in group 2 only 24 patients (36%) experienced acute rejection. However, 8 of 38 patients who experienced rejection in group 1 had the rejection episodes during cyclosporine (CyA) treatment because 19 patients of group 1 converted from tacrolimus to CyA for tacrolimusrelated adverse effects. As a result, rate of acute rejection
Causes of Graft Loss
Among 133 patients, 12 grafts were lost during the observation period. Loss was due to acute rejection in 7 patients, followed by death with function in 2 patients, and chronic rejection, sepsis, and PTLD in 1 patient each.
Fig 2. Graft survival (KaplanMeier).
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TANABE, TOKUMOTO, ISHIKAWA ET AL
Fig 3. Tacrolimus trough levels.
during tacrolimus treatment in group 1 was almost the same, about 37% (Table 2). Complications and Adverse Effects
Table 3 is a summary of complications and adverse effects of tacrolimus. Overall nephrotoxicity occurred in 15% of all patients. Group 2 patients showed significantly lower incidence of nephrotoxicity (3%) than did group 1 patients (27%). Cardiac events, such as chest pain and palpitations, were not frequent in group 2 compared to group 1. Posttransplant diabetes mellitus (PTDM) was not so frequent in this series, which was about 8%, and only 1.5% of the patients required long-term insulin therapy, which is even slightly better than those of CyA-based immunosuppression. Conversion
Because of adverse effects, tacrolimus was converted to CyA in 20% of all recipients. Half of those recipients who had been converted to CyA-based immunosuppression reconverted to tacrolimus, mainly due to rejection. Two of eight patients who had been converted to CyA due to cardiac events were still on CyA treatment; however, six patients were reconverted to tacrolimus owing to acute rejection and recurrence of FSGS. Eleven patients were converted to CyA due to nephrotoxicity. Six of these 11 patients were reconverted to tacrolimus due to rejection or FSGS during CyA treatment. Table 2. Rejection Rates During Tacrolimus Treatment Incidence of Rejection
Overall Group 1 Group 2
(n ⫽ 66) (n ⫽ 67)
(4/96 –12/98) (4/96 –12/98) (1/98 –12/98)
62 (47%) 38 (58%) 24 (36%)
P⫽.019
DISCUSSION
The efficacy of tacrolimus as a primary immunosuppressive agent in renal transplant recipients has been reported in a number of clinical trials.1–5 Reasonable 1- and 3-year patient and graft survival rates of 99% and 97%, and 92% and 90%, respectively, have been achieved. However, there are still some problems, such as malabsorption, nephrotoxicity, PTDM, and cardiac events. Determination of optimal target trough levels of tacrolimus appears to play a key role in solving these problems. Although rejection episodes in group 1 occurred in 38 patients (58%), in group 2 only 24 patients (36%) experienced acute rejection (Table 1). However, 8 of 38 patients who experienced rejection in group 1 had the rejection episodes during CyA treatment, because 19 patients of group 1 converted from tacrolimus to CyA for tacrolimusrelated adverse effects. As a result, rate of acute rejection during tacrolimus treatment in group 1 was almost the same, which was about 37%. This means that high trough levels cause tacrolimus-related adverse effects and the patients were forced to convert to CyA, and eventually got rejection episodes and were forced to reconvert to tacroliTable 3. Complications and Adverse Effects of Tacrolimus Treatment Complication
Group 1 (n ⫽ 66)
Group 2 (n ⫽ 67)
Hypertension Hyperuricemia Nephrotoxicity Hyperlipidemia Posttransplant DM (long-term insulin dependent) CMV disease Cardiac events
19 (29%) 22 (33%) 18 (27%) 10 (15%) 5 (8%) (1) (1.5%) 7 (11%) 6 (9%)
22 (33%) 6 (9%) 2 (3%) 1 (1.5%) 5 (7.5%) (1) (1.5%) 3 (4.5%) 2 (3%)
P
.6132 .0006 .0007 .0042 .9803 .0271 .3027
KIDNEY TRANSPLANT AND TACROLIMUS
mus. From these results, we recommend the lower p.o. tacrolimus dosage and not to convert to CyA for tacrolimusrelated adverse effects. Tacrolimus-induced PTDM is an important adverse event, but is readily reversible with dosage reduction of tacrolimus. Only 1.5% of all patients in this series required long-term insulin therapy, which is the same as that of CyA-based immunosuppressed patients. Incidence of nephrotoxicity was also markedly reduced in group 2 by lowering target trough levels in early period of transplantation. In summary, many significant benefits are associated with tacrolimus-based immunosuppression in renal transplantation and, with increasing experience, the incidence of adverse events can be reduced. We believe that 15 ng/mL of tacrolimus trough level in the induction phase is the optimal concentration.
1699
CONCLUSIONS
Kidney transplantation under tacrolimus immunosuppression after launching in Japan offers an excellent outcome. We conclude that 15 ng/mL of tacrolimus trough level in induction phase seemed to be the optimal concentration.
REFERENCES 1. Starzl TE, Fung JJ, Jordan M, et al: JAMA 63:264, 1990 2. Shapiro R: Transplant Proc 29:45, 1997 3. Woodle ES, Thistlethwaite JR, Gordon JH, et al: Transplantation 62:594, 1996 4. Jordan ML, Shapiro R, Vivas CA, et al: Transplantation 57:860, 1994 5. Japanese FK506 Study Group: Transplant Proc 25:649, 1993