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Experience with tacrolimus as primary immunosuppressor in pediatric liver transplant
STRATEGIES IN LIVER TRANSPLANTATION
Experience With Tacrolimus as Primary Immunosuppressor in Pediatric Liver Transplant M. Asensio, R. Chavez, J. Ortega, J. Iglesias, R. Charco, and C. Margarit
T
ACROLIMUS has been used as an inmunosupressive agent in liver transplantation (LT) during the last 11 years. Wide experience about its efficacy, pharmakokinetics, secondary effects, and toxicity in adults has been reported.1 However, the use of tacrolimus as primary immunosupressant in pediatric patients is more limited.2 The aim of the study was to review our experience with tacrolimus as a primary immunosupressant in pediatric liver transplant patients. MATERIALS AND METHODS We studied retrospectively 32 liver transplants done in 30 pediatric patients between March 1996 and October 2000. Mean age was 54.6 months (range 1 to 240 months); 16 were boys and 14 were girls. Indications for LT were biliary atresia in 14 patients, fulminant hepatic failure in 4, metabolic disorders in 4, neonatal hepatitis in 2, autoimmune hepatitis in 1, and 7 retransplantations (3 for chronic rejection, 2 for acute arterial thrombosis, 1 portal thrombosis, and 1 graft dysfunction following treatment of lymphoma). A whole liver graft was used in 21 cases, whereas a partial graft was transplanted in 11 cases; among these were six split grafts. All patients received double immunosuppressive therapy with tacrolimus and steroids. Tacrolimus was started at a dose of 0.15 mg/kg per day, administered twice daily by the enteral route. The doses were adjusted to reach trough blood levels between 12 and 18 ng/mL during the first 2 months. Thereafter, the target blood level was lowered to less than 10 ng/mL at 1 year. When trough levels of
tacrolimus were low, despiste high drug doses a pharmakokinetic study of tacrolimus was performed. When rapid metabolism of the drug appeared to be the cause of the low trough levels, fluconazole was administered to decrease tacrolimus metabolism by competition for cytochrome P450. In the last 8 patients, basiliximab, a chimeric anti-IL2-R monoclonal antibody, was added either to decrease nephrotoxicity by dose-sparing or by decreasing dependence on tacrolimus during the first days of initial low tacrolimus levels. Methylprednisolone was administrated in tapered doses, with an initial dose of 10 mg/kg per day. Steroids were withdrawn between 4 months and a year following the transplant if graft function was excellent. Acute graft rejection episodes were treated with 10 mg/kg per day steroid bolus over 3 days. If graft dysfunction persisted, mycophenolate mofetil (MMF) was introduced. Monoclonal antibodies (OKT3) were not used in any case. As far as cytomegalovirus (CMV) prophylaxis is concerned, a 10-day treatment with 5 mg/kg per day IV ganciclovir (GCV) was given when both donor and recipient CMV serological status were negative. When either donor or recipient or both were positive, 10 mg/kg per day IV GCV was given over 2 weeks followed by 40 mg/kg per day p.o. until day 100.
From Hospital Vall d’Hebro´n, Barcelona, Spain. Address correspondence to Dr Marino Asensio, Pediatric Surgery Department, Hospital Vall d’Hebro´n, Paseig de la Vall d’Hebro´n 119-129, 08035 Barcelona, Spain.
Table 1. Mean Doses and Levels of Tacrolimus During the Follow-up
Doses Level
Initial
1 Week
2 Weeks
3 Weeks
1 Month
3 Months
6 Months
1Year
3 Years
0.14 ⫾ 0.06 10.8 ⫾ 9.5
0.26 ⫾ 0.21 11.2 ⫾ 4.5
0.35 ⫾ 0.21 13.5 ⫾ 7.7
0.35 ⫾ 0.19 12.3 ⫾ 4.7
0.34 ⫾ 0.18 12.3 ⫾ 4.2
0.32 ⫾ 0.17 12.8 ⫾ 4.3
0.22 ⫾ 0.12 12.3 ⫾ 4.3
0.2 ⫾ 0.09 9.8 ⫾ 2.6
0.07 ⫾ 0.02 4.64 ⫾ 2.97
© 2002 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 34, 105–106 (2002)
0041-1345/02/$–see front matter PII S0041-1345(01)02689-6 105
106
ASENSIO, CHAVEZ, ORTEGA ET AL
Table 2. Patient Percentages With Normal Value for Every Variable in 1- 6-Month, and 1-Year Analytical Posttransplant Controls
Total bilirubin ALT ␥GT Urea Creatinine
1 Month
6 Months
1 Year
46% 52.1% 8.7% 64% 92.3%
75% 72% 60% 64% 100%
90% 91.6% 75% 92% 100%
Normal value: T.B. ⬍1.5 mg/dL; GPT: ⬍50 UI/L; ␥GT: ⬍50 UI/L; urea: ⬍50 mg/dL; creatinine ⬍1.
Tacrolimus doses at different time periods after LT as well as trough drug levels were studied. The incidence of acute and chronic rejection and the severity of rejection episodes were analyzed. Tacrolimus toxicity was studied through the incidence of renal dysfunction, hypertension, diabetes, neurotoxicity, diarrhea, cardiac alterations, lymphoproliferative disorders, and infections. A study of graft function by means of determinations of liver function tests, total bilirubin (TB), ALT and ␥GT levels at 1 month, 3 months, and 1 year posttransplant is presented.
RESULTS
One- and 3-year actuarial patient and graft survival rates were 80% and 70%, respectively; six patients died, three during the postoperative period and three during the follow-up. Causes of death in the postoperative period were hemorrhages due to severe coagulation complications in two cases and a lethal brain aspergilloma in a cystic fibrosis patient (who died 15 days after transplant) of the three patients who died during the follow-up period, one had a complicated posttransplant evolution and finally died from cerebral hemorrhage and the other two died from sepsis. Two retransplants presented as surgical emergencies due to hepatic artery thrombosis; both survived. The mean dose of tacrolimus and levels obtained are shown in Table 1. The initial dose of 0.15 mg/kg per day was progressively increased to a mean dose of 0.35 mg/kg per day at 15 days, at which point the dose was tapered to 0.22 mg/kg per day until 6 months. The maximum mean dose was 0.71 mg/kg per day. In 13 patients, fluconazole was used during the firsts weeks, when the dose was being increased, but adequate levels were not obtained. Steroids were discontinued at 6 months’ posttransplant in 12 patients; at 1 year only three patient’s were still on steroids. Of the 30 patients, 13 showed one or more episodes of acute rejection (43.2% of total patients), but only 2 were steroid resistant. In these two cases MMF was used. An other nine patients received MMF during the follow-up, two as single therapy once tacrolimus was discontinued due to toxicity, are seven within combination therapy to increase inmunosuppression. There was no case of chronic rejection. Tacrolimus was removed in six cases, four were temporarily converted to Neoral cyclosporine. Tacrolimus was
reintroduced in four patients without problem after complications were resolved. In two cases it was discontinued owing to infection, one with cerebral aspergiloma who died, and other with an Epstein-Barr virus infection with polymorphic lymphoproliferative syndrome. Another four cases of toxicity included cardiac arrythmia, chronic diarrhea, neurological crisis, and renal failure. There were no CMV infections in the group. Liver function tests during follow-up are shown in Table 2. One year after LT, 90% of the patients showed normal hepatic function tests, and all of them had normal renal function. DISCUSSION
The present results suggest that tacrolimus and steroids represent a highly effective combination for primary inmunosuppressive therapy in pediatric LT. Almost all the patients could be treated without steroids after the first 6 months posttransplant. Patient survival was similar to other published series.3,4 The incidence of acute graft rejection was relatively high during the first month owing to low tacrolimus blood levels in most cases. However, the majority of acute rejections (85%) responded to steroid treatment.5 Corticoresistant acute rejections were successfully treated with the addition of MMF as triple therapy. Pediatric livers seem to show high activity of cytochrome P450 leading to rapid tacrolimus metabolism in the liver. The doses needed to obtain adequate levels of tacrolimus in blood were high compared with adult series.6 For that reason, fluconazole administration was frequently needed to reach therapeutic blood concentrations, particularly during the first weeks. Good tolerance to the drug was observed and toxicity has been mild.7 No CMV infection or disease was observed in the posttransplant period. Only one case of posttransplant lymphoproliferative disease was diagnosed and treated with withdrawal of immunosuppression and chemotherapy with good outcome. Renal function has been within the normal range in all patients after 1 year, and liver function tests are also excellent. REFERENCES 1. Piyawat K, Mervin HD: Exp Opin Invest Drugs 8:1239, 1999 2. Tzakis AG, Reyes J, Todo S, et al: Transplant Proc 23:3010, 1991 3. Neuhaus P, Klupp J, Langrehr JM, et al: Transplantation 69:2343, 2000 4. Tzakis AG, Reyes J, Todo S, et al: Transplant Proc 25:619, 1993 5. Jara P, Robledo MJ, Frauca E, et al: Transplant Int 11:275, 1998 6. Jain AB, Fung JJ, Tzakis AG, et al: Transplant Proc 23:2763, 1991 7. Reyes J, Jain A, Mazariegos G, et al: Transplantation 12:2573, 2000
Experience With Tacrolimus as Primary Immunosuppressor in Pediatric Liver Transplant M. Asensio, R. Chavez, J. Ortega, J. Iglesias, R. Charco, and C. Margarit
T
ACROLIMUS has been used as an inmunosupressive agent in liver transplantation (LT) during the last 11 years. Wide experience about its efficacy, pharmakokinetics, secondary effects, and toxicity in adults has been reported.1 However, the use of tacrolimus as primary immunosupressant in pediatric patients is more limited.2 The aim of the study was to review our experience with tacrolimus as a primary immunosupressant in pediatric liver transplant patients. MATERIALS AND METHODS We studied retrospectively 32 liver transplants done in 30 pediatric patients between March 1996 and October 2000. Mean age was 54.6 months (range 1 to 240 months); 16 were boys and 14 were girls. Indications for LT were biliary atresia in 14 patients, fulminant hepatic failure in 4, metabolic disorders in 4, neonatal hepatitis in 2, autoimmune hepatitis in 1, and 7 retransplantations (3 for chronic rejection, 2 for acute arterial thrombosis, 1 portal thrombosis, and 1 graft dysfunction following treatment of lymphoma). A whole liver graft was used in 21 cases, whereas a partial graft was transplanted in 11 cases; among these were six split grafts. All patients received double immunosuppressive therapy with tacrolimus and steroids. Tacrolimus was started at a dose of 0.15 mg/kg per day, administered twice daily by the enteral route. The doses were adjusted to reach trough blood levels between 12 and 18 ng/mL during the first 2 months. Thereafter, the target blood level was lowered to less than 10 ng/mL at 1 year. When trough levels of
tacrolimus were low, despiste high drug doses a pharmakokinetic study of tacrolimus was performed. When rapid metabolism of the drug appeared to be the cause of the low trough levels, fluconazole was administered to decrease tacrolimus metabolism by competition for cytochrome P450. In the last 8 patients, basiliximab, a chimeric anti-IL2-R monoclonal antibody, was added either to decrease nephrotoxicity by dose-sparing or by decreasing dependence on tacrolimus during the first days of initial low tacrolimus levels. Methylprednisolone was administrated in tapered doses, with an initial dose of 10 mg/kg per day. Steroids were withdrawn between 4 months and a year following the transplant if graft function was excellent. Acute graft rejection episodes were treated with 10 mg/kg per day steroid bolus over 3 days. If graft dysfunction persisted, mycophenolate mofetil (MMF) was introduced. Monoclonal antibodies (OKT3) were not used in any case. As far as cytomegalovirus (CMV) prophylaxis is concerned, a 10-day treatment with 5 mg/kg per day IV ganciclovir (GCV) was given when both donor and recipient CMV serological status were negative. When either donor or recipient or both were positive, 10 mg/kg per day IV GCV was given over 2 weeks followed by 40 mg/kg per day p.o. until day 100.
From Hospital Vall d’Hebro´n, Barcelona, Spain. Address correspondence to Dr Marino Asensio, Pediatric Surgery Department, Hospital Vall d’Hebro´n, Paseig de la Vall d’Hebro´n 119-129, 08035 Barcelona, Spain.
Table 1. Mean Doses and Levels of Tacrolimus During the Follow-up
Doses Level
Initial
1 Week
2 Weeks
3 Weeks
1 Month
3 Months
6 Months
1Year
3 Years
0.14 ⫾ 0.06 10.8 ⫾ 9.5
0.26 ⫾ 0.21 11.2 ⫾ 4.5
0.35 ⫾ 0.21 13.5 ⫾ 7.7
0.35 ⫾ 0.19 12.3 ⫾ 4.7
0.34 ⫾ 0.18 12.3 ⫾ 4.2
0.32 ⫾ 0.17 12.8 ⫾ 4.3
0.22 ⫾ 0.12 12.3 ⫾ 4.3
0.2 ⫾ 0.09 9.8 ⫾ 2.6
0.07 ⫾ 0.02 4.64 ⫾ 2.97
© 2002 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 34, 105–106 (2002)
0041-1345/02/$–see front matter PII S0041-1345(01)02689-6 105
106
ASENSIO, CHAVEZ, ORTEGA ET AL
Table 2. Patient Percentages With Normal Value for Every Variable in 1- 6-Month, and 1-Year Analytical Posttransplant Controls
Total bilirubin ALT ␥GT Urea Creatinine
1 Month
6 Months
1 Year
46% 52.1% 8.7% 64% 92.3%
75% 72% 60% 64% 100%
90% 91.6% 75% 92% 100%
Normal value: T.B. ⬍1.5 mg/dL; GPT: ⬍50 UI/L; ␥GT: ⬍50 UI/L; urea: ⬍50 mg/dL; creatinine ⬍1.
Tacrolimus doses at different time periods after LT as well as trough drug levels were studied. The incidence of acute and chronic rejection and the severity of rejection episodes were analyzed. Tacrolimus toxicity was studied through the incidence of renal dysfunction, hypertension, diabetes, neurotoxicity, diarrhea, cardiac alterations, lymphoproliferative disorders, and infections. A study of graft function by means of determinations of liver function tests, total bilirubin (TB), ALT and ␥GT levels at 1 month, 3 months, and 1 year posttransplant is presented.
RESULTS
One- and 3-year actuarial patient and graft survival rates were 80% and 70%, respectively; six patients died, three during the postoperative period and three during the follow-up. Causes of death in the postoperative period were hemorrhages due to severe coagulation complications in two cases and a lethal brain aspergilloma in a cystic fibrosis patient (who died 15 days after transplant) of the three patients who died during the follow-up period, one had a complicated posttransplant evolution and finally died from cerebral hemorrhage and the other two died from sepsis. Two retransplants presented as surgical emergencies due to hepatic artery thrombosis; both survived. The mean dose of tacrolimus and levels obtained are shown in Table 1. The initial dose of 0.15 mg/kg per day was progressively increased to a mean dose of 0.35 mg/kg per day at 15 days, at which point the dose was tapered to 0.22 mg/kg per day until 6 months. The maximum mean dose was 0.71 mg/kg per day. In 13 patients, fluconazole was used during the firsts weeks, when the dose was being increased, but adequate levels were not obtained. Steroids were discontinued at 6 months’ posttransplant in 12 patients; at 1 year only three patient’s were still on steroids. Of the 30 patients, 13 showed one or more episodes of acute rejection (43.2% of total patients), but only 2 were steroid resistant. In these two cases MMF was used. An other nine patients received MMF during the follow-up, two as single therapy once tacrolimus was discontinued due to toxicity, are seven within combination therapy to increase inmunosuppression. There was no case of chronic rejection. Tacrolimus was removed in six cases, four were temporarily converted to Neoral cyclosporine. Tacrolimus was
reintroduced in four patients without problem after complications were resolved. In two cases it was discontinued owing to infection, one with cerebral aspergiloma who died, and other with an Epstein-Barr virus infection with polymorphic lymphoproliferative syndrome. Another four cases of toxicity included cardiac arrythmia, chronic diarrhea, neurological crisis, and renal failure. There were no CMV infections in the group. Liver function tests during follow-up are shown in Table 2. One year after LT, 90% of the patients showed normal hepatic function tests, and all of them had normal renal function. DISCUSSION
The present results suggest that tacrolimus and steroids represent a highly effective combination for primary inmunosuppressive therapy in pediatric LT. Almost all the patients could be treated without steroids after the first 6 months posttransplant. Patient survival was similar to other published series.3,4 The incidence of acute graft rejection was relatively high during the first month owing to low tacrolimus blood levels in most cases. However, the majority of acute rejections (85%) responded to steroid treatment.5 Corticoresistant acute rejections were successfully treated with the addition of MMF as triple therapy. Pediatric livers seem to show high activity of cytochrome P450 leading to rapid tacrolimus metabolism in the liver. The doses needed to obtain adequate levels of tacrolimus in blood were high compared with adult series.6 For that reason, fluconazole administration was frequently needed to reach therapeutic blood concentrations, particularly during the first weeks. Good tolerance to the drug was observed and toxicity has been mild.7 No CMV infection or disease was observed in the posttransplant period. Only one case of posttransplant lymphoproliferative disease was diagnosed and treated with withdrawal of immunosuppression and chemotherapy with good outcome. Renal function has been within the normal range in all patients after 1 year, and liver function tests are also excellent. REFERENCES 1. Piyawat K, Mervin HD: Exp Opin Invest Drugs 8:1239, 1999 2. Tzakis AG, Reyes J, Todo S, et al: Transplant Proc 23:3010, 1991 3. Neuhaus P, Klupp J, Langrehr JM, et al: Transplantation 69:2343, 2000 4. Tzakis AG, Reyes J, Todo S, et al: Transplant Proc 25:619, 1993 5. Jara P, Robledo MJ, Frauca E, et al: Transplant Int 11:275, 1998 6. Jain AB, Fung JJ, Tzakis AG, et al: Transplant Proc 23:2763, 1991 7. Reyes J, Jain A, Mazariegos G, et al: Transplantation 12:2573, 2000