Abstract
Although cyclosporine (CsA)-based immunosuppressive regimens have been highly successful in renal transplantation in infants and children, their adverse influence on somatic growth, general appearance, and blood pressure are of particular importance in this population. Over the past 4 years, we have utilized tacrolimus (formerly FK-506) as the primary immunosuppressive agent in 43 unselected children and achieved 1-year and 3-year allograft survival rates of 96% and 85%, respectively. We have also used tacrolimus to rescue 14 of 19 (74%) renal allografts from CsA-resistant rejection. Corticosteroids were discontinued in 62% of non-rescue patients without increasing the risk of rejection or renal dysfunction over a mean follow-up time of 25 months. Tacrolimus monotherapy has been associated with improved body growth and less obesity, while tacrolimus alone or in combination with prednisone was virtually free of hirsutism or gingival hypertrophy, and posed a low risk for hypertension. A major disadvantage of this regimen may be an increased risk for viral infections and a benign form of posttransplant lymphoproliferative disease. This article describes the tacrolimus protocol utilized in our center and focuses on practical clinical issues including therapeutic monitoring, benefits, and major toxicity in children with renal allografts.
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Kino T, Hatanaka H, Miyata S, Inamura N, Nishujama M, Yajima T, Goto T, Okuhara M, Kohsaka M, Aoki H (1987) FK506, a novel immunosupressant isolated from a streptomyces. II. Immuno-suppressive effect of FK506 in vitro. J Antibiot (Tokyo) 40: 1256–1265
Schreier MH, Baumann G, Zenke G (1993) Inhibition of T-cell signaling pathways by immunophilin drug complexes: are side effects inherent to immunosuppressive properties? Transplant Proc 25: 502–507
Fruman DA, Burakoff SJ, Bierer BE (1994) Immunophilins in protein folding and immunosuppression. FASEB J 8: 391–400
Tocci MJ, Matkovich DA, Collier KA, Kwok P, Dumont F, Lin S, Degudicibus S, Siekierka JJ, Chin J, Hutchinson NI (1989) The immunosuppressant FK506 selectively inhibits expression of early T-cell activation genes. J Immunol 143: 718–726
Murase N, Kim DG, Todo S, Cramer DV, Fung J, Starzl TE (1990) Induction of liver, heart, and multivisceral graft acceptance with a short course of FK 506. Transplant Proc 22: 74–75
Ellis D, Shapiro R, Jordan ML, Scantlebury VP, Gilboa N, Hopp L, Weichler N, Tzakis AG, Simmons RL (1994) Comparison of FK-506 and cyclosporine regimens in pediatric renal transplantation. Pediatr Nephrol 8: 193–200
Randhawa PS, Shapiro R, Jordan M, Starzl TE, Demetrius AJ (1993) The histopathological changes associated with allograft rejection and drug toxicity in renal transplant recipients maintained on FK506: clinical significance and comparison with cyclosporine. Am J Surg Pathol 17: 60–68
Fung JJ, Alessiani M, Abu-Elmagd K, Todo S, Shapiro R, Tzakis A, Van Thiel D, Armitage J, Jain A, McCauley J (1991) Adverse effects associated with the use of FK506. Transplant Proc 23: 3105–3108
Firdaous I, Hassoun A, Otte JB, Reding R, Clement de Clety S, Wallemacq PE (1994) Pediatric intravenous FK506-how much are we really infusing. Transplantation 57: 1821–1822
Tamura K, Kobayashi M, Hashimoto K, Kojima K, Nagase K, Iwasaki K, Kaizu T, Tanaka H, Niwa M (1987) A highly sensitive method to assay FK506 levels in plasma. Transplant Proc 19: 23–29
Cadoff EM, Venkataramanan R, Krajack A, Jain AS, Fung JJ, Todo S, Starzl TE (1990) Assay of FK506 in plasma. Transplant Proc 22: 50–51
Beysens AJ, Wijnen RMH, Bluman GH, Heyden J van der, Kootstra G, As H van (1991) FK506 monitoring in plasma or in whole blood? Transplant Proc 23: 2745–2747
Jusko WJ, D'Ambrosio R (1991) Monitoring FK506 concentrations in plasma and whole blood. Transplant Proc 23: 2732–2735
Taormina D, Abdallah HY, Venkataramanan R, Logue L, Burckart GJ, Ptachcinski RJ, Todo S, Fung JJ, Starzl TE (1992) Stability and adsorption of FK506 in 5% dextrose injection and 0.9% sodium chloride injection in glass polyvinyl chloride, and polyolefin containers. Am J Hosp Pharm 49: 119–122
Shaefer MS, Collier DS, Haven MC, Langnas AN, Stratta RJ, Donovan JP, Sorrell MF, Shaw BW (1993) Falsely elevated FK-506 levels caused by sampling through central venous catheters. Transplantation 56: 475–476
Peters DH, Fitton A, Plosker GL, Faulds D (1993) Tacrolimus. A review of its pharmacology, and therapeutic potential in hepatic and renal transplantation. Drugs 46: 746–794
Hooks MA (1994) Tacrolimus, a new immunosuppressant — a review of the literature. Ann Pharmacol 28: 501–510
Tzakis AG, Reyes J, Todo S, Nour B, Shapiro R, Jordan M, McCauley J, Armitage J, Fung JJ, Starzl TE (1993) Two-year experience with FK506 in pediatric patients. Transplant Proc 25: 619–621
Armitage JM, Fricker FJ, Nido P del, Starzl TE, Hardesty RL, Griffith BP (1993) A decade (1982 to 1992) of pediatric cardiac transplantation and the impact of FK 506 immunosuppression. J Thorac Cardiovasc Surg 105: 464–473
Reding R, Wallemacq PE, Lamy ME, Rahier J, Sempoux C, Debande B, Jamart J, Barker A, Sokal E, Ville De Goyet J, Moulin D, Clement de Clety S, Otte JB (1994) Conversion from cyclosporine to FK506 for salvage of immunocompromised pediatric liver allografts. Transplantation 57: 93–100
Shapiro R, Scantlebury BP, Jordan ML, Vivas C, Tzakis AG, Ellis D, Gilboa N, McCauley J, Irish W, Mitchell S, Hakala TR, Simmons RL, Starzl TE (1995) FK506 in pediatric kidney transplantation—primary and rescue experience. Pediatr Nephrol (in press)
The North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) (1994) Annual Report. NAPRTCS Clinical Coordinating Center, SUNY-Health Science Center at Brooklyn. Brooklyn, New York
Krick J (1986) Using the Z score as a descriptor of discrete changes in growth. Nutr Supp Serv 6: 14–16
Hamill PV, Drizd TA, Johnson CL, Reed RB, Roche AF, Moore WM (1979) Physical growth: National Center for Health Statistics percentiles. Am J Clin Nutr 32: 607–629
Mekki Q, Lee C, Aweeka F, Laskow D, Neylan J, Mendez R, Steinmuller D, Schechter P (1993) Pharmacokinetics of tacrolimus (FK506) in kidney transplant patients (abstract). Clin Pharmacol Ther 53: 238
Aweeka FT, Benet LZ, Gambertoglio JG, Peter K, Okudaira N, Kinda J, Vincente F (1993) Comparative pharmacokinetics of orally (po) and intravenously (iv) administered tacrolimus (FK506) in pre- and post-kidney transplant recipients (abstract). Clin Pharmacol Ther 53: 151
Shapiro R, Jordan M, Scantlebury V, Vivas C, Fung JJ, McCauley J, Tzakis A, Randhawa P, Demetris AJ, Irish W, Mitchell S, Jensen C, Jain A, Hakala T, Simmons R, Starzl TE (1994) A prospective randomized trial of FK506 in renal transplantation — a comparison between double and triple drug therapy. Clin Transplant 8: 508–515
Liebowitz D (1995) Epstein-Barr virus — an old dog with new tricks. N Engl J Med 332: 55–57
Knowles DM, Cesarman E, Chadburn A, Frizzera G, Chen J, Rose EA, Michler RE (1995) Correlative morphologic and molecular genetic analysis demonstrates three distinct categories of post-transplantation lymphoproliferative disease. Blood 85: 552–565
Lee ES, Locker J, Nalesnik M, Reyes J, Jaffe R, Alashari M, Nour B, Tzakis A, Dickman PS (1995) The association of Epstein-Barr virus with smooth-muscle tumors occurring after organ transplantation. N Engl J Med 332: 19–25
Kuo PC, Dafoe DC, Alfrey EJ, Sibley RK, Scandling JD (1995) Posttransplant lymphoproliferative disorders and Epstein Barr virus prophylaxis. Transplantation 59: 135–138
Swinnen LJ, Costanzo-Nordin MK, Fisher SG, O'Sullivan EJ, Johnson MR, Heroux AL, Dizikes GJ, Pifarre R, Fisher RI (1990) Increased incidence of lymphoproliferative disorder after immunosuppression with the monoclonal antibody OKT3 in cardiac transplant recipients. N Engl J Med 323: 1723–1728
Alfrey EJ, Friedman AL, Grossman RA, Perkoff LJ, Naji A, Barker CF, Montone KT, Tomaszewski JE, Chmielewski C, Holland T (1992) A recent decrease in the time to development of monomorphous and polymorphous posttransplant lymphoproliferative disorder. Transplantation 54: 250
Hibberd PL, Rubin RH (1991) Prevention of cytomegalovirus infection in the pediatric renal transplant recipient. Pediatr Nephrol 5: 112–117
Carroll PB, Rilo H, Reyes J, Alejandro R, Zeng Y, Ricordi C, Tzakis A, Shapiro R, Starzl TE (1991) FK 506-associated diabetes mellitus in the pediatric transplant population is a rare complication. Transplant Proc 23: 3171–3172
Krentz AJ, Dousset B, Mayer D, McMaster P, Buckels J, Cramb R, Smith JM, Nattrass M (1993) Metabolic effects of cyclosporin-A and FK 506 in liver transplant recipients. Diabetes 42: 1753–1759
Scantlebury V, Shapiro R, Fung J, Tzakis A, McCauley J, Jordan M, Jensen C, Hakala T, Simmons R, Starzl TE (1991) New onset of diabetes in FK 506 vs cyclosporine-treated kidney transplant recipients. Transplant Proc 23: 3169–3170
Jindal RM, Popescu I, Schwartz ME, Emre S, Boccagni P, Millet CM (1994) Diabetogenicity of FK506 versus cyclosporine in liver transplant recipients. Transplantation 58: 370–372
Jindal RM (1994) Posttransplant diabetes mellitus — a review. Transplantation 58: 1289–1298
Tauxe WN, Mochizuki T, McCauley J, Starzl TE, Jain A, Charron M (1991) A comparison of the renal effects (ERPF, GFR and IF) of FK 506 and cyclosporine in patients with liver transplantation. Transplant Proc 23: 3146–3147
Ueda A, Tajima A, Ohtawara Y, Ishikawa A, Nakano M, Ushiyama T, Ohta N, Kawabe K, Aso Y (1991) Influence of FK 506 on renal blood flow. Transplant Proc 23: 3121–3122
Moutabarrik A, Ishibashi M, Fukunaga M, Kameoka H, Takano Y, Kokado Y, Takahara S, Jiang H, Sonoda T, Okuyama A (1991) FK 506 mechanism of nephrotoxicity: stimulatory effect on endothelin secretion by cultured kidney cells and tubular cell toxicity in vitro. Transplant Proc 23: 3133–3136
Moutabarrik A, Ishibashi M, Kameoka H, Ogata A, Kawaguchi N, Takano Y, Kokado Y, Takahara S, Jiang H, Onishi S, Sonoda T, Okuyama A (1991) In vitro FK 506 kidney tubular cell toxicity. Transplant Proc 23: 3137–3140
Venkataramanan R, Jain A, Warty VW, Abu-Elmagd K, Furakawa H, Imventarza O, Fung J, Todo S Starzl TE (1991) Phamacokinetics of FK506 following oral administration: a comparison of FK506 and cyclosporine. Transplant Proc 23: 931–933
McCauley J, Fung J, Jain A, Todo S, Starzl TE (1990) The effects of FK 506 on renal function after liver transplantation. Transplant Proc 22: 17–20
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Ellis, D. Clinical use of tacrolimus (FK-506) in infants and children with renal transplants. Pediatr Nephrol 9, 487–494 (1995). https://doi.org/10.1007/BF00866738
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DOI: https://doi.org/10.1007/BF00866738