Tacrolimus-Basiliximab Versus Cyclosporine-Basiliximab in Renal Transplantation “De Novo”: Acute Rejection and Complications D. Martin Garcia, J. Martin Gago, A. Mendiluce, R. Gordillo, and J. Bustamente ABSTRACT Background. Optimal immunosuppression is essential to maintain kidney allograft viability but minimizing toxicity is also fundamental. Objective. This article compares immunosuppressants, corticosteroids, cyclosporine, tacrolimus, and basiliximab, which are used in the treatment regimens for renal transplantation. The analyses evaluated their effectiveness to prevent acute rejection episodes and to reduce the appearance of other complications, mainly infectious disease complications. Methods. Ninety-five patients were analysed during the first year after primary renal transplantion. These patients were included in a random way in 3 different groups according to the immunosuppressant drug therapy: Group I (35 patients) received corticosteroids ⫹ CsA; Group II (35 patients) received corticosteroids ⫹ CsA ⫹ Basiliximab; Group III (25 patients) received corticosteroids ⫹ Tacrolimus ⫹ Basiliximab. Results. Among the 95 patients, 9 presented with an acute rejection episode in Group I. None in Group II, and one in group III. With reference to the infectious disease complications, the incidence of oral herpes was one case in Group I, 4 cases in Group II, and 2 cases in group III. Conclusions. Treatment with Basiliximab produced a significantly lower incidence of acute rejection cases and an increase in infectious disease complications, such as lip herpes.
HE MAIN OBJECTIVE of immunosuppressant drug therapy is the prevention of kidney allograft rejection while minimizing the complications of infectious and neoplasic morbidities. Since 1960 steroids have been used in immunosuppressant treatments for kidney transplantation. Their actions include direct inhibition of interleukin (IL-1) synthesis and indirect blockade of IL-2 release. They are used fundamentally during the induction phase, in combination with Cyclosporine (CsA) or Tacrolimus.1 In high doses they may be used for acute rejection treatment.2 Azathioprine is an imidazole derivative of 6-mercaptopurine, a purine analogue. It was the immunosuppressant drug used before the arrival of CsA. It has been used in combination with CsA or Tacrolimus as a third drug, mainly in cases where CsA or Tacrolimus have produced nephrotoxicity. It is not useful for the treatment of acute rejection episodes.3 Nowadays, after the appearance of new immunosuppressant drugs like Mycophenolate, the use of Azathioprine has decreased. Mycophenolate Mofetil (MMF), an ester of mycophe-
nolic acid (MPA) is a noncompetitive, reversible inhibitor of inosine-monophosphate dehydrogenase (IMPDH). Its inhibition reduces guanine synthesis and DNA replication. The main indication for the use of MMF is prevention of acute rejection. It is also useful for treatment of corticosteroid-resistant acute rejection episodes and may prevent or slow the progression of chronic rejection.4 – 6 MMF has been developed as a substitute for Azathioprine in induction therapy. There are contradictory data about whether it is beneficial for chronic rejection. CsA, an endecapeptide, has high immunosuppressive activity to inhibit the transcription of genes encoding the synthesis of IL-2, IL-3, IL-4, ␣TNF, and gamma interferon.7 The oral absorption of the drug shows inter- and intraFrom the Nephrology Department, University Hospital, Valladolid, Spain. Address reprint requests to D. Martin Garcia, Nephrology Department, University Hospital, Nephrology Department, c/o Ramon Y Capal # 3 Valladolid, Spain.
0041-1345/03/$–see front matter doi:10.1016/S0041-1345(03)00576-1
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Transplantation Proceedings, 35, 1694 –1696 (2003)
TACROLIMUS-BASILIXIMAB VS CSA-BASILIXIMAB
individual variability, requiring the monitoring of drug levels to adjust the dose.8 –10 The recommended exposures are shown by concentrations (unit: g/L): during the first month the 2 hour postdose concentration (C2) 1.700; 2nd month: C2 ⫽ 1.500; 3rd month: C2 ⫽ 1.300, 4th to the 6th month: C2 ⫽ 1.100, 7th to the 12th month C2 ⫽ 900, after the 12 month: C2 ⫽ 800 g/L. CsA is biotransformed in the liver by the cytochrome P-450 III-A enzymatic system to form numerous metabolites. This process is affected by numerous other drugs. Nowadays, CsA is used as primary immunosuppression due to improved short- and long-term kidney allograft survival.11 In the face of posttransplantation acute tubular necrosis, some investigators delay the introduction of CsA because it may retard tubular epithelial regeneration and prolong allograft dysfunction.12 Thus, the most important adverse effect is nephrotoxicity.13 Tacrolimus, a macro cyclic compound obtained from Streptomyces tsukubaensis, was described by Kino et al in 1984. Although structurally it is different from CsA, both prodrugs act by inhibiting cytokine synthesis, thereby blocking T-cell activation, proliferation, and cytotoxic element generation. It also reduces the growth and differentiation of B cells by interfering with the expression of IL-4 and IL-5. Its immunosuppressive capacity is greater than that of CsA.14 Determination of Tacrolimus levels is used to monitor the drug,15,16 which is also metabolized in the liver through cytochrome P450 IIIA and eliminated in the bile. It is used as a primary immunosuppressant for prevention of acute rejection and also as a rescue treatment for corticosteroid-resistant rejection. Nowadays it is the best alternative to the CsA for baseline immunosuppression. Among the monoclonal antibodies, OKT3 shows the greater immunosuppressant efficacy in the clinical field. The antibodies are directed against a marker on all T lymphocytes. It has been used mainly for the treatment of corticosteroid-resistant acute rejection episode, as well as in some induction protocols.17 Basiliximab (Simulect), an antibody of murine immunoglobulin (Ig)G origin, is directed against the alpha chain of the IL-2 receptor.18 It has been used for induction therapy in kidney transplantation in combination with steroids and CsA or Tacrolimus for the prophylaxis of an acute rejection episode. It is well tolerated without important secondary effects.19 The objective of our study was to compare 3 different immunosuppressive treatments for “de novo” kidney transplants for their outcomes during the first posttransplantation year, effectiveness to prevent the incidence of acute rejection episodes, and appearance of other complications. PATIENTS AND METHODS Among the 95 patients, 3 groups were separated, according to the immunosuppressive treatment: Group I, CsA and corticosteroids; Group II, CsA, corticosteroids, and basiliximab; and Group III, corticosteroids, tacrolimus, and basiliximab. Group I included 35 patients with a mean age of 44 ⫾ 12 years.
1695 Table 1. Results During Follow-up in the First Year
Recipient age Donor age Cold Ischemia (h) Acute rejection Lip herpes
Group I (n ⫽ 35)
Group II (n ⫽ 35)
Group III (n ⫽ 25)
44 ⫾ 12 46 ⫾ 18 19 ⫾ 4 9 1
58 ⫾ 10 52 ⫾ 17 18 ⫾ 4 0 4
53 ⫾ 13 60 ⫾ 8 18 ⫾ 4 1 2
They were administered CsA (8 mg/kg/d), which was subsequently adjusted according to levels. Corticosteroids were administered at a dose of 0.5 mg/kg/d on the first day after kidney transplantation with the dose reduced until reaching 10 mg/d by the 6th month as the maintenance dose. The mean age of the 35 patients in Group II was 58 ⫾ 10 years. The CsA and corticosteroids were administered at the same doses as in Group I but basiliximab was added. It was administered in 2 intravenous doses of 20 mg each: the first dose before and the second dose, 4 days after the transplantation. Group III, including 25 patients, showed a mean age of 53 ⫾ 13 years. They received Tacrolimus beginning at a dose of 0.2 mg/kg/d and adjusted according to levels; a corticosteroid dose of 0.3 mg/kg/d, which was smaller than the previous groups, and reduced to maintenance dose of 5 mg/day on the 3rd month after transplantation. The 3rd agent was basiliximab administered at the same doses as administered in Group II.
Table 1 shows the results obtained during follow-up in the first year after the transplantation. While there were no significant differences among the 3 groups for recipient or donor age or for cold ischemia time, there was a higher incidence of acute rejection among Group I (9 cases of acute rejection) patients. In contrast, the incidence of lip herpes was significantly greater among Groups II and III, (4 and 2 cases, respectively). DISCUSSION
Immunosuppressive treatment of patients who have undergone transplantation includes new potent agents whose use has been based more on their short-term impact than their long-term benefits. Chronic rejection of the renal allograft is not affected, but these agents do pose threats of cardiovascular illness, cancer and infections, particularly for longterm survival.20 The monoclonal antibodies, such as Basiliximab, are designed to prevent, but cannot treat acute rejection episodes when they are used in combination with CsA or Tacrolimus and corticosteroids. They are of low immunogenicity and do not show significant secondary toxicities.21 Groups II and III who received Basiliximab (Simulect) showed a significant decrease in episodes of acute rejection compared to with Group I who did not receive Basiliximab. There were no significant differences between Group II who received Corticosteroids ⫹ CsA ⫹ Simulect and Group III who were administered Corticoids ⫹ Tacrolimus ⫹ Simulect in terms of the incidence of acute rejection
episodes. With respect to the infectious complications, the appearance of lip herpes, herpes simple virus,22,23 which is manifested typically during the first 6 weeks after transplantation, Groups II and III, who received Simulect, showed a significantly greater incidence than Group I who did not receive Simulect. REFERENCES 1. Ratcliffe PJ, Deudley CRK, Higgins RM: Lancet 348:643, 1996 2. Hricik DE, Almwi WY, Strom TB: Transplantation 57:979, 1994 3. Helderman JH, Van Buren DH, Amend WJ Jr, et al: J Am Soc Nephrol 4(suppl I):S2, 1994 4. Allison AC, Eugui EM, Sollinger HW: Transplant Rev 7:129, 1993 5. European Mycophenolate Mofetil Cooperative Study Group: Lancet 345:1321, 1995 6. Sollinger HW for the US Renal Transplant Mycophenolate Mofetil Study Group: Transplantation 345:1321, 1995 7. Ichikura H, Tanabe K, Tokumota T, et al: Transplant Proc 32:1733, 2000 8. Keown P, Landsberg D, Halloran P, et al: Transplantation 62:1744, 1996
MARTIN, MARTIN, MENDILUCE ET AL 9. Kahan BD, Sahw LM, Holt D, et al: Clin Chem 36:1510, 1990 10. Levy GA: bioDrugs 15:279, 2001 11. Jordan ML, Sahpiro R, Vivas SA: Transplantation 57:860, 1994 12. Calne RY, White DJ, Thiru S, et al: Lancet 2:1323, 1978 13. Flechner SM, Van Buren C, Kerman R, et al: Transplant Proc 15:2689, 1983 14. Pirsch JD, Miller J, Deierhoi MH: Transplantation 63:977, 1997 15. Venkataramanan R, Swaminathan A, Prasad T, et al: Clin Pharmacokinet 29:404, 1995 16. Japanese FK506 Study Group: Transplant Proc 23:3085– 3088, 1991 17. Opelz G: Transplantation 60:1220, 1995 18. Nashan B, Moore R, Amlot P, et al: Lancet 350:1193, 1997 19. Kahan BD, Rajagopalan PR, Hall M: Transplantation 67: 276, 1999 20. Heldeman JH, Goral S: In Danovitch GM (ed): Handbook of Kidney Transplantation, 3rd ed. Philadelphia: Lippincott, Williams and Wilkins, 2000, p 17 21. Danovitch GM: In Danovitch GM (ed): Handbook of Kidney Transplantation, 3rd ed. Philadelphia: Lippincott, Williams and Wilkins, 2000, p 90 22. Tolkoff-Rubin NE, Rubin RH: Semin Nephrol 20:148, 2000 23. Rubin RH: Kidney Int 44:221, 1993