ORIGINAL ARTICLE
Year : 2013 | Volume
: 24 | Issue : 3 | Page : 473--479
Basiliximab induction in renal transplantation: Long-term outcome
Mahendra Atlani, Raj K Sharma, Amit Gupta
Department of Nephrology, SGPGIMS, Lucknow, India
Correspondence Address:
Mahendra Atlani
Department of Nephrology, Bhopal Memorial Hospital and Research Center, Bhopal - 462 038
India
Abstract
Anti-IL-2 receptor has been proven to be effective in reducing the rate of acute rejection in kidney transplantation and also in improving the graft and patient survival rates. In this study, we retrospectively reviewed the role of the anti-IL-2 receptor, basiliximab, as an induction immunosuppression. Fifty-seven kidney transplant recipients from living donors who received the IL-2 blocker basiliximab (Group 1) as induction therapy in combination with cyclosporine (CsA), steroids and mycophenolate mofetil (MMF) or azathioprine (AZA) were compared with similarly matched renal transplant recipients (N = 312) who did not receive induction therapy (Group 2). Survival analysis was performed using the Kaplan-Meir method. Chi-square test was used to compare the outcome difference of various parameters between the two groups. Both the groups were similar in terms of demographic charateristcs and maintenance immunosuppression used. The total number of rejections was significantly less in Group 1, 14% vs 25% in Group 2 (P = 0.04, Odds ratio = 0.44). A higher number of patients in Group 2 had steroid-resistant rejections, although the difference was not statistically significant (9.9% in Group 2 vs 5.3% in Group 1). Death-censored graft survival was not significantly better in Group 1 at five years as compared with Group 2 (79.4% vs 47.2%, P = 0.09). On multivariate analysis for association with graft survival, only late acute rejections and steroid-resistant rejections were independently associated with poor graft survival, while the type of maintenance immuno-suppression (MMF vs AZA), use of basiliximab induction therapy and total number of acute rejection episodes had no association. Our study suggests that the use of anti-IL-2 receptor antibody basiliximab as induction immuno-suppression results in significantly better prevention of acute rejection, but it does not result in a significantly improved graft survival at five years. It also results in reduced severity of acute rejection.
How to cite this article:
Atlani M, Sharma RK, Gupta A. Basiliximab induction in renal transplantation: Long-term outcome.Saudi J Kidney Dis Transpl 2013;24:473-479
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How to cite this URL:
Atlani M, Sharma RK, Gupta A. Basiliximab induction in renal transplantation: Long-term outcome. Saudi J Kidney Dis Transpl [serial online] 2013 [cited 2023 Jan 29 ];24:473-479
Available from: https://www.sjkdt.org/text.asp?2013/24/3/473/111010 |
Full Text
Introduction
Acute rejection is one of the strongest predictors of long-term graft survival following renal transplantation. [1],[2] Rejection occurring during the first year after renal transplant almost halves the projected graft half-life. [3] Since 1995, the rates of acute rejection have fallen dramatically; for example, the incidence of acute rejection during the first six months post-transplant has declined from over 40% in 1995 to around 15% in 2000. [4] Part of this improvement results from increased use of induction therapy with the introduction of more selective induction agents, particularly the interleukin-2 receptor antagonists (IL-2RA), basiliximab and daclizumab. These are now widely used in many transplant centers, [4] , [5] either routinely or for high-risk individuals.
Basiliximab is a monoclonal antibody (IgG1 k ) produced by recombinant DNA technology. It binds with and blocks the IL-2R α-chain, also known as CD25 antigen, on the surface of activated T lymphocytes. This competitively inhibits the binding of serum IL-2 to CD25, thereby inhibiting the proliferation of activated T cells and subsequent release of cytokines. Administration of IL-2RA induction also leads to down-regulation of IL-2R expression, which in turn alters circulating lymphocyte distribution. Basiliximab is a chimeric antibody, i.e. it is composed of variable domains of the original mouse monoclonal antibody and the constant regions of human immunoglobulin. Basiliximab has a high affinity for CD25 and its license states two fixed doses of 20 mg for adults, one given on the day of transplant and one on Day four after transplant. [6] Using this dosage schedule, the CD25 subunit remains saturated with basiliximab for approximately five to eight weeks after transplantation. [6]
Addition of an IL-2RA to a variety of calcineurin inhibitor-based immunosuppressive regimens reduces acute rejection by 30-50% as reported in two meta-analyses of the randomized controlled trials. These meta-analyses also demonstrated trends toward improved graft survival with IL2R antibodies compared with no induction, but these differences did not reach statistical significance. [7],[8] A large-scale analysis of data from the United Network for Organ Sharing (UNOS) has reported that graft survival improved by 17% (P = 0.002) with the addition of IL-2RA induction compared with no induction at 727 days. [9] The favorable side-effect profile of IL-2RA, including the apparent lack of any increased risk of cytomegalovirus (CMV) infection or malignancy, [9] is a notable advantage.
Almost all prospective studies of induction with IL-2R antibodies in renal transplantation have involved patients on cyclosporine (CyA) and azathioprine (AZA). It has been suggested that the benefit of IL-2R antibodies might not be evident with immunosuppressive regimens based on tacrolimus (TAC) and mycophenolate mofetil (MMF), because these regimens are more potent in preventing rejection. Because most renal transplant recipients are currently maintained on TAC and MMF, it is important to determine the efficacy of IL2R antibodies co-administered with these newer drugs.
The aim of the present study was to analyze the efficacy of basiliximab used for induction treatment compared with no induction at five years post-transplantation.
Patients and Methods
This longitudinal observational study analyzed data from 369 live donor renal transplant patients from a single center in India. All adult patients aged between 18 and 65 years, who received a primary or secondary renal transplant between 2001 and 2006, were included in this study. Patients were treated with CyA, AZA/MMF and steroids. Two treatment groups were defined based on whether a patient had received basiliximab or not. Patients were followed-up from the initial transplantation date until reaching a study end point. The primary end point was death censored graft survival. Secondary outcomes were rejection, patient survival and incidence of infection and malignancy. Rejection was defined as a patient who was recorded as being treated for acute rejection. Late acute rejections were defined as rejections occurring after three months of transplant; all acute rejections were treated with 500 mg i.v. methylprednisolone for three days. No response to this therapy was recorded as steroid-resistant rejections and was treated with ATG/OKT3.
Log-rank statistics were used to compare the Kaplan Meier survival curves between patients treated with basiliximab and patients receiving no induction treatment following transplantation. Multivariate Cox regression models were used to investigate the independent effect of the primary treatment regimen on the safety and efficacy end points between the two populations studied. Multivariate analyses were adjusted for induction therapy, MMF-based maintenance immunotherapy, type of living donor, related (haplotype matched) or unrelated (non-haplo-type matched), donor and recipient age, donor and recipient gender and retransplant status. Chi square analysis was used to compare the incidence rates of acute rejection between treatment regimens. An alfa level of 0.05 (type 1 error) was used as the cutoff value for statistical significance. Statistical analyses were performed with SAS version 13.
Results
[Table 1] shows the demographic characteristics of the two study groups. Both groups were similar with respect to the demographic characteristics. The basiliximab group included 57 patients (Group 1), while 312 patients did not receive this induction therapy (Group 2). [Table 2] summarizes the comparison between the two groups in the overall clinical outcome.{Table 1}{Table 2}
Rejection
Early acute rejection rates were significantly lower in Group 1 patients (14%) when compared with patients in Group 2 (25%) (P = 0.04). Additionally, patients in Group 1 also had a lower prevalence of steroid-resistant rejections as compared with patients in Group 2 (5.3% vs 9.9%, respectively). There was a trend toward lower prevalence of late acute rejections in Group 1 patients, but it did not reach statistical significance. The five-year univariate Cox regression for acute rejections showed that basiliximab significantly reduced the risk for acute rejection compared with patients who did not receive induction treatment (HR = 0.44; 95% CI 0.21-0.92; P = 0.031).
Graft survival
According to the Kaplan Meier analysis, basiliximab therapy did not significantly improve the death censored graft survival at five years, although there was a trend toward positive benefit without statistical significance (79.4% vs 47.2% in Groups 1 and 2, respectively, P = 0.09, [Figure 1]. At five years post-transplant, there were lesser numbers of graft loss in patients treated with basiliximab induction compared with patients who did not receive this drug (4.6% vs 9.4%, P = 0.16). The five-year Cox regression (univariate) analysis revealed that basiliximab and MMF-based immunosuppression reduced the risk for graft loss at five years (HR 0.37; 95% CI 0.115-1.2 and HR 0.66; 95% CI 0.32-1.3, respectively). However, neither showed statistical significance on multivariate analysis [Table 3] and [Table 4].{Figure 1}{Table 3}{Table 4}
Patient survival
Patient survival at five years was not significantly different in the two groups of patients; 88% vs 94% in Group 1 and Group 2, respectively (P = 0.53, [Figure 2]). At five years post-transplant, 3.1% of the patients in Group 1 and 3.8% of the patients in Group 2 died (P = 0.56). The five-year Cox regression (univariate) analysis revealed that basiliximab treatment did not significantly reduce the risk for patient death as compared with no treatment (HR 0.63; 95% CI 0.150-2.6; P = 0.53).{Figure 2}
Renal function
At five years, there was no significant difference in renal function in the two groups of patients. Chronic allograft nephropathy (serum creatinine >1.5 mg%) was present in 56.7% of the patients in Group 2 and 43.1% of the patients in Group 1.
Infection and malignancy
Among patients in Group 2, 2.2% developed CMV disease, 0.8% developed tuberculosis, 1% developed herpes zoster and 0.4% developed cryptococcal meningitis during the five-year follow-up. On the other hand, in the Group 1 patients, 1.7% developed active tubercular infection and 5.3% (3/57) developed CMV disease. No patient in the basiliximab group developed zoster or cryptococcal infection. None of the study patients in either group developed malignancy.
Discussion
In this study, we report the long-term follow-up analysis of the effect of IL2R Ab basiliximab on acute rejection and graft survival after renal transplantation. We found that basiliximab significantly reduced the occurrence of acute rejection episodes compared with no induction at three months (14% for basiliximab vs 25% for no induction P = 0.04), consistent with the findings of prior randomized control trials, [10],[11],[12],[13],[14],[15],[16],[17],[18] meta-analyses [7],[8] and retrospective database analyses. [9] Basiliximab therapy also significantly reduced the severity of acute rejections, which was similar to results reported in meta-analyses. [7] Also, there was a trend toward reduced occurrence of late acute rejections at five years post-transplant in the basiliximab group, despite the presence of a larger number of patients with immunologic high risk such as re-transplants in the induction group (3.5% vs 1.3%) and more living unrelated donor transplants (35.9% vs 25.5%).
We also found improved graft survival at five years in Group 1 patients compared with patients in Group 2. Similar findings have been reported by a few other authors. [9],[19] Sheashaa et al did not find improved graft survival at five years in their small study population [20] (N = 50 each, with and without induction).
While basiliximab induction was associated with improved graft survival at five years on univariate analysis (HR 0.29; 95% CI 0.091- 0.921), the association was lost on multivariate analysis. MMF-based immunosuppression was also associated with improved graft survival on univariate analysis, but this was lost significance on multivariate analysis (HR 0.56; 95% CI 0.30-1.04).
We did not find a significantly different patient survival at five years between the two study groups (88% in Group 1 and 94% in Group 2, P = 0.53). The mortality rate at five years was also not significantly different (3.1% and 3.8%, respectively, in Groups 1 and 2, P = 0.50). Similar outcomes for patient survival have been reported by Webster et al [7] and Sheashaa et al. [20]
The occurrence of infection was slightly higher in patients who received basiliximab induction. A study presented at the American Transplant Congress in 2004 reported increased risk of death due to infections in patients given IL-2Rb. However, an apparent lack of increased risk of CMV infection or malignancy [9] has also been reported. The apparent increased risk in our study could be related to the small number of patients developing these infections in both groups.
We conclude that basiliximab induction does not significantly increase graft survival at five years post-transplant. However, the benefit in terms of significant reduction of early acute rejections as well as reduction of severity of acute rejections was reconfirmed.
Conflict of interest: None
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