Effective Immunoprophylaxis With Basiliximab Plus Triple Therapy in Renal Transplantation: Five-Year Single-Center Experience A. Kandus, K. Grego, M. Arnol, D. Kovacˇ, J. Lindicˇ, J. Buturovic´, R. Ponikvar, and A.F. Bren ABSTRACT We studied prospectively the efficacy and safety of basiliximab combined with triple immunosuppression in adult recipients of ⱖ1 HLA-mismatched deceased donor renal grafts. All studied patients received equal immunosuppressive drugs: 20 mg infusion of basiliximab on day 0 and on day 4, cyclosporine microemulsion (Neoral), mycophenolate mofetil, and methylprednisolone. An analysis of 1-year data assessed the incidence of acute rejection episodes, safety of this therapy, renal graft function, and patient and graft survivals. One hundred seventy-two patients were studied. The HLA-antigen mismatches were 2.9 ⫾ 0.9 (mean ⫾ SD), and the cold ischemia time was 22.0 ⫾ 7.5 hours. Fifty-three (31.5%) patients experienced delayed graft function. At 12 months, 5 (3.0%) patients experienced acute rejection. Six renal grafts were lost, but not from rejection. Two patients died. Sixty-six infections required treatment in the hospital. One carcinoma of cervix (in situ) and two basal cell carcinomas of skin were detected. Hypersensitivity reactions and cytokine-release syndrome were not observed. At 12 months, serum creatinine was significantly higher (119 ⫾ 46 mol/L; P ⬍ .001) in patients with delayed graft function than in patients with immediate graft function (99 ⫾ 26 mol/L). Patient and graft survivals were 98.8% and 97.1%, respectively. Basiliximab combined with this triple therapy was an efficient and safe immunosuppression strategy, demonstrated with very low incidence of acute rejections, an acceptable adverse event profile, excellent graft function, and high short-term survival rates in adult recipients of deceased donor renal transplant.
ASILIXIMAB, a chimeric (human and mouse) antiinterleukin-2 receptor monoclonal antibody, is used to supplement standard immunosuppressive therapy after renal transplantation. It binds with high specificity and affinity to the alpha subunit (CD25) of the interleukin-2 receptor on activated T lymphocytes. When combined with basiliximab, interleukin-2 receptors are not available for interleukin-2 binding, and proliferation of the activated T cell is inhibited.1,2 At a dose of 20 mg administered intravenously before transplantation and on day 4, basiliximab maintains interleukin-2 receptor saturation for 4 to 6 weeks.1–3 The average duration of this saturation was prolonged by 39% and 64% in the presence of azathioprine and mycophenolate mofetil, respectively.4 Basiliximab is proven to be effective for acute rejection prophylaxis after renal transplantation,5– 8 and was well tolerated in clinical trials.5–9 The incidence of infections and other adverse events was similar between treatment groups.5– 8 Basiliximab was minimally immunogenic.1 Moreover, economic
analysis demonstrated that it offers a cost-effective therapeutic benefit.10 These favorable results justify the use of basiliximab in combination with triple therapy. In a prospective study, we assessed efficacy and safety of basiliximab combined with cyclosporine (CsA), mycophenolate mofetil, and methlylprednisolone in deceased donor renal graft recipients over a 12-month follow-up. PATIENTS AND METHODS
All studied adult recipients of ⱖ1 HLA-mismatched deceased donor kidneys transplanted at our medical center from October 1999 through September 2004 received the From the University Medical Center, Department of Nephrology, Ljubljana, Slovenia. Address reprint requests to Prof Aljosa Kandus, PhD, MD, University Medical Center, Zaloka cesta 7, Ljubljana, Slovenia 1000. E-mail: [email protected]
© 2006 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/06/$–see front matter doi:10.1016/j.transproceed.2006.08.142
Transplantation Proceedings, 38, 2853–2855 (2006)
KANDUS, GREGO, ARNOL ET AL
same prophylactic immunosuppressive drugs: 20 mg infusion of basiliximab (Simulect, Novartis, Basel, Switzerland) on day 0 about 2 hours before transplantation and again on day 4. Continuous infusion of CsA (0.08 mg/kg per hour) was started at time of operation and replaced by CsA microemulsion (Neoral) at 3 mg/kg twice a day on day 2. Mycophenolate mofetil at 1 g twice a day (0.75 g twice a day in patients with body weight ⬍50 kg) was started on day 1. From June 2002, mycophenolate mofetil was given at 0.75 g three times a day (0.5 g three times a day in patients with body weight ⬍50 kg). Methylprednisolone (0.4 mg/kg) was injected at operation and from day 1 through day 3. Oral methylprednisolone (0.4 mg/kg per day) was begun on day 4 and tapered by 4 mg per week to achieve maintenance dose of 0.08 mg/kg per day. Until June 2002 CsA Neoral dose was adjusted to maintain blood trough levels of 150 to 250 ng/mL during first 3 months after transplantation and 100 to 200 ng/mL after the third month. CsA concentration was measured by fluorescence polarization immunoassay (monoclonal antibodies). From June 2002 enzymemultiplied immunoassay technique was used. Target blood CsA trough levels ranged from 100 to 170 ng/mL during first 3 months and 70 to 130 ng/mL after the third month. All patients received diltiazem from day 0. Clinical evaluations of vital signs, graft function, laboratory variables, as well as patient and graft survivals were made regularly during follow-up. Graft function was monitored by serum creatinine. Graft core biopsy was performed in all suspected cases of acute rejection. Unless otherwise stated, the presented data are expressed as means ⫾ standard deviations (SD). Significance was assessed with the t test for unpaired data. Patient and Table 1. Characteristics of Patients and Donors (n ⴝ 172) Recipient age (y) Mean ⫾ SD Range Recipient gender [n (%)] Male Female Recipient race [n (%)] Caucasian Donor age (y) Mean ⫾ SD Range Donor gender [n (%)] Male Female HLA-antigen mismatches (n) Mean ⫾ SD Range Latest PRA value (%) Mean ⫾ SD Range Cold ischemia time (h) Mean ⫾ SD Range PRA, panel-reactive antibody.
46 ⫾ 10 18–65 102 (59.3) 70 (40.7) 172 (100) 37 ⫾ 14 6–61 97 (56.4) 75 (43.6) 2.9 ⫾ 0.9 1–5 8 ⫾ 13 0–85 22.0 ⫾ 7.5 7.0–41.0
Table 2. Blood CsA Trough Levels (ng/mL, Mean ⴞ SD) Day
3 4 5 6 7 14 30 60 90 365
261 ⫾ 87 267 ⫾ 74 256 ⫾ 65 246 ⫾ 63 237 ⫾ 65 210 ⫾ 48 212 ⫾ 53 195 ⫾ 43 184 ⫾ 48 142 ⫾ 32
188 ⫾ 73 182 ⫾ 60 176 ⫾ 62 176 ⫾ 48 170 ⫾ 51 149 ⫾ 49 153 ⫾ 42 130 ⫾ 33 132 ⫾ 34 97 ⫾ 18
FPIA, fluorescence polarization immunoassay; EMIT, enzyme-multiplied immunoassay technique.
graft survivals were calculated using the Kaplan-Meier technique. The study was approved by the Ethical Committee of our institution. Informed consent was obtained from each patient. RESULTS
Among 172 study patients, 15 (8.7%) received a second renal graft. Seventy-six (44.2%) kidneys were local in origin; 96 (55.8%) kidneys were shipped from other Eurotransplant centers. The characteristics of patients and donors are presented in Table 1. Fifty-three (31.5%) patients experienced delayed graft function, defined as need for posttransplant dialysis. Thrombotic microangiopathy was diagnosed upon biopsy of four patients with insufficient posttransplant improvement of graft function. Renal graft function improved after reduction of CsA Neoral dose. CsA Neoral doses (mg/kg) on days 30, 60, 90, and 365 were as follows: 2.9 ⫾ 0.9, 2.6 ⫾ 0.8, 2.4 ⫾ 0.8, 1.9 ⫾ 0.6. Blood CsA trough levels are presented in Table 2. During 12-months followup; 5 (3.0%) of 168 patients (excluding those with never functioning graft) experienced acute rejection. Three of them had suffered delayed graft function. All rejections occurred after the third month and were successfully treated. Six renal grafts were lost. The causes of graft loss were as follows: early renal vein thrombosis (n ⫽ 4) and death of patient (n ⫽ 1). One renal graft with excellent function was removed on day 10 because of metastatic bronchial carcinoma detected at the autopsy of the donor. Transplant rejection was excluded by histopathological examination of explanted grafts after early renal vein thrombosis. Two patients died: one patient with functioning graft because of sepsis after cecal perforation in week 5 and one patient because of cerebral infarction in week 7. The infections requiring treatment in the hospital are presented in Table 3. Eleven patients developed posttransplant diabetes mellitus. Basal cell carcinoma of skin was detected in two patients and carcinoma of cervix (in situ) in one. Hypersensitivity reactions and cytokine-release syndrome were not observed. Serum creatinine concentrations (mol/L) on days 30, 60, 90, and 365 were as follows: 113 ⫾ 40, 112 ⫾ 36, 110 ⫾ 36, 105 ⫾ 35. At 12 months, serum creatinine was significantly higher (119 ⫾ 46 mol/L; P ⬍
BASILIXIMAB PLUS TRIPLE THERAPY
Table 3. Infections Requiring Hospitalization During the 12-Month Posttransplant Period Infections
Patients [n (%)]
Cytomegalovirus Varicella-zoster virus Herpes simplex virus Candida BK virus nephritis Pyelonephritis/UTI Septicemia Pneumonia (bacterial) Wound infection Cholecystitis
14 (8.1) 4 (2.3) 2 (1.2) 1 (0.6) 1 (0.6) 29 (16.9) 9 (5.2) 4 (2.3) 1 (0.6) 1 (0.6)
UTI, urinary tract infection.
.001) in patients who suffered delayed graft function than the serum creatinine in patients who had immediate graft function (99 ⫾ 26 mol/L). Patient and graft survivals were 98.8% and 97.1%, respectively. DISCUSSION
Therapy with basiliximab in combination with CsA Neoral, mycophenolate mofetil, and methylprednisolone seems to be a promising immunosuppressive strategy due to the absence of early acute rejection episodes and low overall incidence of acute rejections. In addition, total methylprednisolone dose during the first posttransplant week was three times lower, and the dose was tapered faster than in our previous therapy. Furthermore, initial CsA Neoral dose and target blood CsA levels were also lower than they had been previously.11 Beside of the high efficacy of this therapy, lower steroid and CsA doses could possibly decrease the frequency and severity of adverse effects of these two drugs. In a multicenter, randomized, double-blind, placebocontrolled study of basiliximab given with triple therapy, an analysis was performed after 6-month follow-up. The incidence of biopsy-proven acute rejection in the basiliximab group was 15.3%.8 The higher acute rejection rate in comparison with our results was somewhat surprising, because patients were given higher doses of CsA Neoral and they maintained higher CsA trough levels, and some patients received higher doses of mycophenolate mofetil and steroids. This discrepancy in results could not be explained by different tissue compatibility, which was very similar and also far from optimal in our patient group. We might speculate that the routine use of diltiazem, the compulsory negative historical crossmatch, the high level of medication compliance, and the Caucasian race of all our patients
contributed to better results. The incidence of serious infections was comparable to our results. Supporting the efficacy and safety of our immunosuppression were excellent renal graft function, even in patients who suffered delayed graft function, and high survival rates at the end of a 12-month follow-up. We conclude that basiliximab combined with CsA Neoral, mycophenolate mofetil, and methylprednisolone is an efficient and safe immunosuppression strategy, demonstrated with very low incidence of acute rejections, an acceptable adverse events profile, excellent graft function, and high survival rates over the first 12 posttransplant months in adult recipients of deceased donor renal transplant. REFERENCES 1. Onrust SV, Wiseman LR: Basiliximab. Drugs 57:207, 1999 2. Maes BD, Vanrenterghem YF: Anti-interleukin-2 receptor monoclonal antibodies in renal transplantation. Nephrol Dial Transplant 14:2824, 1999 3. Kovarik JM, Kahan BD, Rajagopalan PR, et al: Population pharmacokinetics and exposure-response relationships for basiliximab in kidney transplantation. Transplantation 68:1288, 1999 4. Kovarik JM, Pescovitz MD, Sollinger HW, et al: Differential influence of azathioprine and mycophenolate mofetil on the disposition of basiliximab in renal transplant patients. Clin Transplant 15:123, 2001 5. Nashan B, Moore R, Amlot P, et al: Randomised trial of basiliximab versus placebo for control of acute cellular rejection in renal allograft recipients. Lancet 350:1193, 1997 6. Kahan BD, Rajagopalan PR, Hall M: Reduction of the occurrence of acute cellular rejection among renal allograft recipients treated with basiliximab, a chimeric anti-interleukin2-receptor monoclonal antibody. Transplantation 67:276, 1999 7. Ponticelli C, Yussim A, Cambi V, et al: A randomized, double-blind trial of basiliximab immunoprophylaxis plus triple therapy in kidney transplant recipients. Transplantation 72:1261, 2001 8. Lawen JG, Davies EA, Mourad G, et al: Randomized doubleblind study of immunoprophylaxis with basiliximab, a chimeric anti-interleukin-2 receptor monoclonal antibody, in combination with mycophenolate mofetil-containing triple therapy in renal transplantation. Transplantation 75:37, 2003 9. Kovarik J, Wolf P, Cisterne JM, et al: Disposition of basiliximab, an interleukin-2 receptor monoclonal antibody, in recipients of mismatched cadaver renal allografts. Transplantation 64:1701, 1997 10. Keown PA, Balshaw R, Krueger H, Baladi JF: Economic analysis of basiliximab in renal transplantation. Transplantation 71:1573, 2001 11. Kovacˇ D, Kotnik V, Kandus A: Basiliximab and mycophenolate mofetil in combination with low-dose cyclosporine and methylprednisolone effectively prevent acute rejection in kidney transplant recipients. Transplant Proc 37:4230, 2005