Objectives: Basiliximab is used alongside tacrolimus-based immunosuppression for routine induction therapy, even for well-matched living-donor renal transplant recipients. Because tacrolimus is a different drug from cyclosporine, this study examined the utility of tacrolimus-based immunosuppression without basiliximab for well-matched living-donor renal transplant recipients.
Material and Methods: This prospective study evaluated 36 patients who underwent 1 to 3 human leukocyte antigens mismatched living-donor renal transplants without basiliximab induction therapy between April 2012 and March 2015 (group 1). All transplants were ABO compatible and T-flow negative and were followed until April 2015. Tacrolimus-based triple therapy was used for maintenance immunosuppression. The control group comprised 72 age- and sex-matched patients who underwent 1 to 3 human leukocyte antigens mismatched living-donor renal transplants with basiliximab induction therapy during the same period (group 2).
Results: Two patients in group 1 and 12 patients in group 2 had infection,with cytomegalovirus infection and Pneumocystis pneumonia infection occurring only in group 2 and BK virus and urinary tract infection reported in both groups, with a similar incidence. One patient from group 2 had sepsis. Although the incidence of infection tended to be lower in group 1 than in group 2 (5.6% vs 16.7%), the overall incidence of infection was not significantly different (P=.135). In addition, there were no significant differences in incidence of acute rejection between groups 1 and 2 (2.8% vs 4.2%; P=.699). All patients showed stable renal function after treatment.
Conclusions: Tacrolimus-based triple drug maintenance immunosuppression without basiliximab might be an optimal treatment choice for individuals undergoing well-matched living-donor renal transplant.
Key words : Kidney transplantation, Tacrolimus, Basiliximab
Basiliximab is a chimeric mouse-human monoclonal antibody specific for the alpha chain (CD25) of the interleukin 2 receptor. When bound to its receptor, interleukin 2 activates intracellular signaling pathways that induce T-cell proliferation and play a key role in triggering transplant rejection. Thus, basiliximab prevents the activation of effector cells that drive alloimmune responses by inhibiting activation of the interleukin 2 receptor.1 Randomized controlled trials have compared basiliximab with placebo in cases of kidney transplant performed under cyclosporine-based immunosuppression. The incidence of acute rejection was significantly lower in the basiliximab-treated arm, although the incidence of infection and other adverse events was generally similar between the 2 arms.2,3 These trials showed that basiliximab is routinely used alongside tacrolimus-based immunosuppression as an agent for induction therapy even in patients who have well-matched living-donor renal transplants in Korea. Some centers in other countries omit induction therapy for such transplants, but no prospective study has examined the safety of such protocols. In addition, the clinical efficacy of tacrolimus plus basiliximab remains unclear because tacrolimus is a different drug from cyclosporine and is a more potent immunosuppressant.4,5 Therefore, the aim of the present study was to examine the utility of tacrolimus-based immunosuppression in the absence of basiliximab induction therapy in well-matched living-donor renal transplant recipients.
Materials and Methods
Study design and patients
This study prospectively evaluated 36 patients who underwent 1 to 3 HLA-mismatched living-donor renal transplants without basiliximab induction therapy between April 2012 and March 2015 (group 1). All transplants were ABO compatible and T-flow negative and were followed until April 2015. Maintenance immunosuppression comprised tacrolimus-based triple therapy (tacrolimus, mycophenolate mofetil, and methylprednisolone). Zero mismatch transplants were excluded because cyclosporine was used in those cases. The control group comprised 72 age- and sex-matched patients who underwent 1 to 3 HLA-mismatched living-donor renal transplants with basiliximab induction therapy during the same period (group 2).The control group received 20 mg of basiliximab on the day of surgery and on postoperative day 4, alongside tacrolimus-based triple therapy. The study was approved by the local institutional ethics committee (2013-0209) and was carried out in accordance with the Declaration of Helsinki. Informed consent was obtained from all individual participants included in the study.
Definition of infection
Patients were screened for cytomegalovirus (CMV) and BK virus infections, urinary tract infections, pneumonia, and sepsis (all classed as major infectious events). Cytomegalovirus infection was diagnosed when the CMV antigenemia assay showed > 50 cells/200,000 white blood cells. The patient was then treated with ganciclovir. The CMV antigenemia assay was performed using the Light Diagnostic CMV pp65 Antigenemia kit (Chemicon International, Temecula, CA, USA). Polymerase chain reaction to detect BK virus was performed using the Real-Q BK virus quantification kit (BioSewoom, Seoul, Korea). BK virus infection was diagnosed when the plasma DNA load was > 10,000 copies/mL. Urinary tract infection was diagnosed when urine cultures showed significant bacterial growth (> 105 colony-forming units/mL) and the patient was treated with antibiotics. A diagnosis of pneumonia was based on clinical symptoms and chest radiographs. Sepsis was defined as systemic inflammatory response syndrome, with a positive blood culture. All patients received oral trimethoprim/sulfamethoxazole (80/400 mg) for 6 months postoperatively for Pneumocystis pneumonia prophylaxis. Cytomegalovirus prophylactics were not given routinely because the Korean nationwide insurance system does not support oral valganciclovir prophylaxis (except when a donor’s CMV IgG is positive and recipient’s CMV IgG is negative). However, preemptive therapy was performed based on serial monitoring of CMV antigenemia.
Diagnosis of rejection
Rejection was suspected clinically when serum creatinine levels began to rise. Rejection was confirmed by renal biopsy. Protocol biopsies were not performed routinely. C4d staining was performed on all specimens using standard immunofluorescence techniques. Acute rejection was diagnosed according to the Banff criteria.
Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 21.0, IBM Corporation, Armonk, NY, USA). Data are expressed as means ± standard deviation. Categorical variables were compared using the chi-squared test or Fisher exact test. Continuous variables were compared using t test or the Mann-Whitney U test. Acute rejection-free survival was estimated using the Kaplan-Meier method and the log-rank test. All statistical tests were two-tailed, with P < .05 considered statistically significant.
Baseline clinical characteristics of the patients
Thirty-six patients were included in group 1 (no basiliximab induction therapy), and 72 patients were included in group 2 (basiliximab induction therapy). The baseline characteristics of the patients are shown in Table 1. There were more men than women in both groups. There were no significant differences between the groups in terms of other characteristics, such as cause of end-stage renal disease. The mean follow-up time was 18.28 ± 11.27 months for group 1 and 17.42 ± 11.26 months for group 2.
Incidence of infection
Two patients (5.6%) in group 1 and 12 patients (16.7%) in group 2 (P = .135) had infections. Cytomegalovirus infection occurred only in group 2. One patient (2.8%) in group 1 and 3 patients (4.2%) in group 2 had BK virus infection. In total (group 1 + group 2), there were 3 cases of urinary tract infection, all occurring between 1 and 2 months after transplant. The identified infectious organisms were Enterobacter cloacae, extended-spectrum beta-lactamase Klebsiella pneumoniae, and extended-spectrum beta-lactamase Escherichia coli. Pneumonia only occurred in group 2. There was 1 patient with Pneumocystis pneumonia infection in group 2, occurring in a 46-year-old male patient who was admitted with pneumonia. Pneumocystis pneumonia was diagnosed by immunocytochemical analyses of bronchoalveolar lavage fluid. The patient recovered after antibiotic therapy, which included trimethoprim-sulfamethoxazole. Sepsis was noted in 1 patient in group 2. Bacteroides fragilis was identified in blood cultures and was well controlled with antibiotics. There tended to be a lower incidence of infection in group 1, although total incidence was not significantly different between the groups (Table 2).
Graft rejection and survival
There was 1 patient with acute T-cell-mediated rejection in group 1 and 3 patients in group 2 (Table 3), although there was no significant difference in rejection-free survival between the groups (Figure 1). All were treated with steroid pulse therapy. An allograft biopsy from 1 patient in group 2 showed evidence of early acute antibody-mediated rejection in addition to acute T-cell-mediated rejection. He was treated with steroid pulse therapy, rituximab, and plasmapheresis. All patients who experienced graft rejection had stable renal function at follow-up. There was no significant difference in serum creatinine levels between the 2 groups (Table 4 and Figure 2). There was no graft loss or mortality. In addition, no cases of malignancy have been reported thus far.
The need for immunosuppressive therapy for kidney transplant recipients means that patients have a lifelong risk of complications and a considerable economic burden. However, because tacrolimus is different from cyclosporine (and a more potent immunosuppressant), we hypothesized that well-matched living-donor renal transplants would be tolerable in the absence of basiliximab induction therapy.4,5 Here, we examined a group of patients who had undergone 1 to 3 HLA-mismatched, ABO-compatible living-donor kidney transplants without basiliximab induction therapy and compared these patients with a group of similar patients who had received basiliximab induction therapy.
Two small-scale studies examined the efficacy of a basiliximab plus tacrolimus-based immunosuppressive regimen for kidney transplant.6,7 Sugiyama and associates7 used a lymphocyte immunosuppressant sensitivity test to evaluate the pharmacologic efficacy of tacrolimus in recipients treated with tacrolimus either with or without basiliximab. Acute rejection was less common in recipients treated with tacrolimus plus basiliximab (7.7% vs 37.5%). However, recipients treated with tacrolimus plus basiliximab showed higher rates of CMV reinfection than recipients treated with tacrolimus alone, although the results were not statistically significant. De Sandes-Freitas and associates6 retrospectively reviewed data from 134 patients who received tacrolimus plus basiliximab and 132 patients who received tacrolimus alone. There was no difference in the incidence of acute rejection, graft loss, CMV infection, or death between the groups. The present prospective study showed similar results. Although CMV infection was only reported in group 2, the result was not significant. In addition, the incidence of acute rejection was not higher for recipients treated with tacrolimus-based immunosuppressantsin the absence of basiliximab induction therapy.
Basiliximab showed relatively good tolerability1; indeed, no significant basiliximab-related adverse effects have been reported in studies comparing basiliximab with placebo in recipients receiving cyclosporine-based immunosuppressants. Nashan and associates3 monitored the safety and tolerability of basiliximab over a 12-month period. The incidence of infection and other adverse events was similar in the basiliximab and placebo groups. The acute tolerability of basiliximab was excellent, with no evidence of cytokine-release syndrome. Ponticelli and associates8 reported that the incidence of adverse events (88% vs 87%), malignancy (1.8% vs 3.5%), and CMV infection (17% vs 14%) was similar in the basiliximab and placebo groups. However, some case studies reported anaphylactic reactions after exposure to basiliximab.9-11 These reactions were reported both on initial exposure to basiliximab and on reexposure.11 According to the Novartis product prescribing information, other acute hypersensitivity reactions have been reported in patients treated with basiliximab.12 These reactions include hypotension, tachycardia, cardiac failure, dyspnea, wheezing, bronchospasm, respiratory failure, urticaria, rash, and pruritus.12 The biologic mechanism or mechanisms underlying these adverse effects are unclear.13 Basiliximab-related noncardiogenic pulmonary edema has also been reported.14,15 Another study reported that the incidence of infection was lower in basiliximab-treated patients than in patients receiving rabbit antithymocyte globulin16; however, it was not clear whether basiliximab induction therapy increased the infectious risk. Here, we found that no patient suffered a hypersensitivity reaction after exposure to basiliximab; however, infectious events tended to occur more frequently in group 2, although the results were not statistically significant. Although the results do not confirm that patients not receiving basiliximab induction therapy are less likely to suffer infection, they do show that well-matched living-donor renal transplant can be performed safely in the absence of basiliximab induction therapy when tacrolimus-based maintenance immunosuppressants are used.
This study has several limitations. First, the number of patients was small. However, because the study is of prospective design, many potential biases were excluded, which may partially compensate for the low patient numbers. Second, the enrolled patients belonged to a single ethnic group. Therefore, the results may not be generalizable. Third, patient follow-up was quite short. We did find that there was an increased tendency toward infection in the basiliximab-treated group, although the result was not statistically significant. A longer follow-up could have resulted in significant differences in the 2 groups. Therefore, a large scale study with longer follow-up is needed to confirm the effects of basiliximab.
In conclusion, tacrolimus-based triple-drug maintenance immunosuppression in the absence of basiliximab might be an optimal treatment for patients undergoing well-matched living-donor renal transplant.
Volume : 14
Issue : 4
Pages : 389 - 393
DOI : 10.6002/ect.2015.0271
From the 1Division of Nephrology, Department of Internal Medicine,
and the 2Department of Surgery, Asan Medical Center, University of
Ulsan College of Medicine, Seoul, Republic of Korea
Acknowledgements: The authors have no sources of funding and no conflicts of interest to declare.
Corresponding author: Su-Kil Park, Division of Nephrology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine,88, Olympic-ro 43-Gil, Songpa-gu, 138-736, Seoul, Republic of Korea
Table 1. Baseline Characteristics
Table 2. Incidence of Infection
Table 3. Incidence of Acute Rejection
Table 4. Serum Creatinine Level
Figure 1. Rejection-Free Survival
Figure 2. Serum Creatinine Levels