|Year : 2019 | Volume
| Issue : 3 | Page : 202-209
Utility of induction agents in living donor kidney transplantation
Radhika Chemmangattu Radhakrishnan1, Gopal Basu2, Anjali Mohapatra3, Suceena Alexander3, Anna T Valson3, Shibu Jacob3, Vinoi George David3, Santosh Varughese3, Tamilarasi Veerasami3
1 Department of Pediatric Nephrology, Government Medical College, Thiruvananthapuram, Kerala, India
2 Renal Medicine, The Alfred Hospital, Monash University, Melbourne, VIC, Australia
3 Department of Nephrology, Christian Medical College, Vellore, Tamil Nadu, India
|Date of Submission||09-Jun-2019|
|Date of Decision||29-Jul-2019|
|Date of Acceptance||28-Aug-2019|
|Date of Web Publication||17-Sep-2019|
Dr. Gopal Basu
The Alfred Hospital, Monash University, 55 Commercial Road, Melbourne, VIC 3004
Source of Support: None, Conflict of Interest: None
Aim: The outcome and long-term adverse events associated with induction agent use for living donor (LD) kidney transplantation (KT) in India were studied. Materials and Methods: Consecutive LD kidney transplant recipients (KTRs) from 2005 to 2013 were studied. They were divided based on induction agent use, into induction group and no induction group. The induction group was further subdivided into those receiving antithymocyte globulin (ATG group) and those receiving basiliximab (IL-2RB group). Study subjects were also classified into high and low immunological risk groups. Outcomes evaluated were patient and graft survival, acute rejections, infections, leucopenia, malignancy, new-onset diabetes mellitus, antibody-mediated rejections, and 1-year serum creatinine. Results: Of 605 LD-KTRs, 445 (73.6%) received induction. 403 (90.6%) received basiliximab induction. There was significant improvement in patient and graft survival in induction group (log rank P = 0.041 and 0.024, respectively), but this benefit disappeared when adjusting for immunosuppressive regimen as well as when only patients on tacrolimus-mycophenolate (Tac-MPA) were considered. There was significant reduction in acute rejections, tuberculosis (TB), and BK viremia in the induction group even in patients receiving Tac-MPA. There was no significant difference between basiliximab and ATG except for increased risk of BK viremia with ATG. Conclusions: The use of induction agents is associated with reduced incidence of acute rejections and serious infections (TB and BK viremia). The survival benefit of induction agent use is lost with the Tac-MPA-based immunosuppression. Thus, induction agent use is not essential for better survival if using Tac-MPA-based regimen.
Keywords: Antithymocyte globulin, basiliximab, induction, interleukin-2 receptor blocker, kidney transplantation
|How to cite this article:|
Radhakrishnan RC, Basu G, Mohapatra A, Alexander S, Valson AT, Jacob S, David VG, Varughese S, Veerasami T. Utility of induction agents in living donor kidney transplantation. Indian J Transplant 2019;13:202-9
|How to cite this URL:|
Radhakrishnan RC, Basu G, Mohapatra A, Alexander S, Valson AT, Jacob S, David VG, Varughese S, Veerasami T. Utility of induction agents in living donor kidney transplantation. Indian J Transplant [serial online] 2019 [cited 2019 Oct 19];13:202-9. Available from: http://www.ijtonline.in/text.asp?2019/13/3/202/266942
| Introduction|| |
Induction agents are widely used in the west with reports suggesting that 83% of kidney transplants in US receive induction. Many biological agents have been found to reduce the incidence of acute rejection in the first 6 months of kidney transplantation (KT) compared to historical standard of methylprednisolone pulse induction and maintenance with prednisolone, cyclosporine, and azathioprine. In spite of these benefits, there is no evidence that induction agent use improve long-term patient and graft survival in the era of modern immunosuppression. In addition, there is always a fear of predisposition to infections in developing countries like India, where more grafts are lost to infection-related patient deaths than rejection. The cost of biological induction agents is also a concern in these countries. Among the available depleting and nondepleting antibodies, no agent has been clearly proven to be superior. We did a retrospective study to assess the impact of induction agent use in living donor (LD)-KT in India and to compare the effects of anti-thymocyte globulin (ATG) and basiliximab as induction agents.
| Materials and Methods|| |
We studied consecutive kidney transplant recipients (KTRs) from January 2005 to December 2013 at our center. Data were collected using the hospital transplant registry database, and additional information was obtained by reviewing transplant charts and electronic medical records. The center performs LD transplants with about 20% having high immunologic risk (defined as nil human leukocyte antigen [HLA] matches and/or crossmatch positivity and/or second transplants) which is the common profile of transplants in the developing countries. HLA desensitization protocol transplants and ABO incompatible transplants were excluded from this analysis due to complex pretransplant immunosuppressive use in the protocols that would confound the results.
The study subjects were grouped into induction group and no induction group based on whether induction agent was used or not. The induction group was further subdivided based on whether ATG or interleukin (IL) 2 receptor blocker (basiliximab) was used for induction, into ATG group and IL-2RB group. The study subjects were also divided into high and low immunological risk groups. High immunologic risk was defined as having one of the following features: (1) historical crossmatch positivity (as ascertained by the HLA laboratory and the treating clinician as positive - either by complement-dependent cytotoxicity, flow or Luminex crossmatch), (2) nil match for HLA A and B antigens, and (3) second or more transplants. ATG group received a single dose of 5 mg/kg r-ATG (Thymogam, Sanofi) as an infusion over 6–8 h about 12 h before transplant surgery. Basiliximab group received two doses of basiliximab (Simulect, Novartis), each dose containing 20 mg of basiliximab as an infusion over 1h about 6 h before surgery and on the fifth posttransplant day. Outcomes evaluated were patient survival, graft survival, acute rejections, infections, leucopenia, malignancy, new-onset diabetes mellitus after transplantation (NODAT), antibody-mediated rejections (AMR), 1-year serum creatinine, and 1-year 24-h urine protein excretion. Outcomes were compared between no induction and induction groups among all KTRs as well as in low immunologic risk group and between ATG and basiliximab groups in high immunologic risk groups. Due to change in the standard maintenance immunosuppression protocols in the institution over the years, data were also analyzed among the select group of patients receiving a tacrolimus (Tac), mycophenolate (MPA), and steroid-based regime.
Statistical analysis was done using SPSS 15.0 software (SPSS Inc., Chicago, IL, US, 2006). Chi-square test and Fischer's test were used for comparison of nonpaired categorical data. Mann–Whitney test was used to compare medians of two independent samples. Graft and patient survivals were analyzed using Kaplan–Meier analysis and Cox proportional hazards model.
| Results|| |
Six hundred and five LD-KTRs with a mean age of 35.2 ± 11.9 years and male: female ratio of 3.5:1 were followed up for a mean duration of 46.2 ± 29.5 months (median – 42.2 months, range 0.03–116.2 months). The native kidney disease was unknown in 357 (59%), diabetic nephropathy in 80 (13.2%), immunoglobulin A nephropathy in 29 (4.8%), focal segmental glomerulosclerosis in 18 (3%), chronic glomerulonephritis in 40 (6.6%), and urological disease in 31 patients (5.1%). Mean donor age was 41.7 ± 11.0 with male: female ratio of 1.8:1. Donors were parents for 218 KTRs (36%), siblings for 192 (31.7%), spouse for 129 (21.3%), children for 23 (3.8%), and other relatives for 43 (7.1%). The distribution of KTRs into various study groups is depicted in [Figure 1]. There was a change in the maintenance immunosuppression protocol over time. The standard immunosuppression regime till early 2006 comprised of prednisolone, cyclosporine (CsA), and azathioprine (Aza). Tac, MPA, and steroids were the standard immunosuppression from late 2006 till end of the study. A total of 440 patients received Tac-MPA-based regime.
|Figure 1: Distribution of living donor kidney transplant recipients into groups based on induction agent use and immunologic risk|
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Induction versus no induction in all kidney transplant recipients
Overall, 445 patients received induction therapy (induction group) and the rest 160 patients did not (no induction group). The baseline characteristics of these 2 groups [Table 1] reveal that patients in the induction group were significantly older and more often had high immunological risk, more likely to have received Tac-MPA based immunosuppression and cytomegalovirus (CMV) prophylaxis with valganciclovir compared to the no induction group; overall, KTRs who received induction had better patient and graft survival than those who did not receive induction (log rank P = 0.041 and 0.024, respectively) [Figure 2]a. There was reduction in acute rejections (18.9% vs. 26.3%, P = 0.049) and lower median serum creatinine at 1-year posttransplant (1.2 [0.6%–4.2%] mg/dL vs. 1.3 [0.7%–9.3%] mg/dL) in the induction group compared to no induction group. There were no differences in AMR, multiple rejections, leucopenia, malignancy, or NODAT among the 2 groups [Table 1]. However, there was significantly lower tuberculosis (TB) infection (6.1% vs. 13.1%, P = 0.05) and a trend toward lower systemic fungal infections (3.8% vs. 7.5%, P = 0.062) in the induction group.
|Table 1: Characteristics of all living donor kidney transplant recipients - induction versus no induction groups and interleukin-2 receptor blocker versus antithymocyte globulin groups|
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|Figure 2: (a) Patient and graft survival in induction and no induction groups in all living donor kidney transplant recipients. (b) Patient and graft survival in induction and no induction groups in all kidney transplant recipients receiving tacrolimus-mycophenolate-based immunosuppressive regimen. (c) Patient and graft survival in induction and no induction groups in low immunologic risk kidney transplant recipients. (d) Patient and graft survival in induction and no induction groups in low immunologic risk kidney transplant recipients receiving tacrolimus-mycophenolate-based immunosuppressive regimen|
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When analyzed by cox proportional hazards model using induction agent use and Tac-MPA-based regimen as variable, induction agent use was not independently associated with better survival [Table 2]. Among KTRs who exclusively received Tac-MPA based maintenance immunosuppression, those in the induction group had similar patient and graft survival compared to those in the no-induction group [Figure 2]b. However, those in induction group continued to enjoy significantly lower acute rejections (18.3% vs. 31.9%, P = 0.032), TB (5.6% vs. 17%, P = 0.009), and BK viremia (7.1% vs. 17%, P = 0.042) but a higher incidence of leukopenia (37.1% vs. 23.4%, P = 0.042) [Table 3].
|Table 2: Cox proportional hazards model for outcome of death and graft loss - induction agent use and tacrolimus/mycophenolate mofetil-based regimen|
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|Table 3: Outcomes of living donor-kidney transplant recipients receiving tacrolimus-mycophenolate - induction versus no induction groups in all kidney transplant recipients and low immunologic risk|
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Antithymocyte globulin versus basiliximab in all kidney transplant recipients
Among the patients who received induction, 42 KTRs received ATG while 403 received basiliximab as induction therapy. On comparing their baseline characteristics, ATG group had female preponderance (male: female ratio 1.6:1 vs. 3.7:1, P = 0.012), significant history of prior blood transfusions (57.5% vs. 39%, P = 0.024), and more high immunologic risk transplants (57.1% vs. 20.6%, P < 0.001) compared to IL-2RB group [Table 1]. Among the high immunologic risk factors, second transplants (7.5% vs. 1%, P = 0.021) and crossmatch positivity (47.6% vs. 3%, P < 0.001) were more prevalent in the ATG. On comparing their outcomes, there was no difference in patient and graft survival between the ATG and IL-2RB groups [Figure 3]a. ATG group had significantly better serum creatinine values at 1 year but also higher BK viremia (14.3% vs. 6.2%, P = 0.050) and a tendency toward more NODAT (33.3% vs. 21.1%, P = 0.069). There were no significant differences in acute rejections, AMR, multiple rejections, leukopenia, malignancy, or other infections among the two groups.
|Figure 3: (a) Patient and graft survival in IL2RB and antithymocyte globulin induction groups in all kidney transplant recipients. (b) Patient and graft survival in antithymocyte globulin and IL2RB groups in high immunologic risk. (c) Patient and graft survival in antithymocyte globulin and basiliximab groups in high immunologic risk patients receiving tacrolimus-mycophenolate-based regimen|
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Induction versus no induction in low immunologic risk transplants
Of 485 low immunologic risk transplants, 338 patients were given induction before transplant whereas 147 KTRs did not receive induction agent. The induction group was significantly younger in age (32.0 ± 10.7 years vs. 34.6 ± 12.0 years, P = 0.023) and received Tac-MPA-based immunosuppression (P < 0.05) and CMV prophylaxis with valganciclovir (P < 0.05) compared to the no induction group who received CsA-Aza-based immunosuppression and no CMV prophylaxis [Table 4]. Among low immunologic risk KTRs, those receiving induction had better overall patient survival [log rank P = 0.008, [Figure 2]c with no difference in graft survival, acute rejections, AMR or multiple rejections, leukopenia, NODAT, and malignancies compared to the no induction group. There was significantly decreased incidence of TB (5.3% vs. 13.6%, P = 0.002) and systemic fungal infections (3.6% vs. 8.2%, P = 0.031) in induction group compared to noninduction group. However, among the Tac-MPA patients, there were no significant differences between these two groups either in terms of patient and graft survival [Figure 2]d. However, those receiving induction had significantly lower TB (4.6% vs. 20%, 0.002) and a trend toward lower rejections (18.5% vs. 32.5%, P = 0.057) and lower BK viremia (7.6% vs. 17.5%, P = 0.066) [Table 3].
|Table 4: Characteristics of induction and no induction groups in low immunologic risk transplants|
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Antithymocyte globulin versus basiliximab in high immunologic risk transplants
Of the 107 high immunologic risk transplants, 24 KTRs received ATG and 83 received basiliximab. Among the high-risk transplant recipients, ATG group had a larger proportion of recipients who were cross-match positive (83.3% vs. 14.5%, P < 0.001) whereas IL-2RB group comprised mainly of poorly HLA matched transplant (HLA AB nil match) recipients [Table 5]. There was no significant difference in maintenance immunosuppression drugs or CMV prophylaxis between these two groups. Among the outcome measures, there was no significant difference in graft or patient survival [Figure 3]b, acute rejections, AMR, multiple rejections, 1-year serum creatinine, 1-year 24-h proteinuria or infections between these groups. There was no statistically significant difference in any of the infections among the groups. Once again, there was a tendency toward higher NODAT incidence among patients receiving ATG (1.6% vs. 20.8%, P = 0.069). There were no differences between ATG and IL2RB groups in rejections, infections, or patient and graft survival within the Tac-MPA subgroup as well [Table 6] and [Figure 3]c.
|Table 5: Characteristics of interleukin-2 receptor blocker and antithymocyte globulin groups in high immunologic risk transplants|
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|Table 6: Outcomes of interleukin-2 receptor blocker and antithymocyte globulin groups in high immunologic risk transplants receiving tacrolimus and mycophenolate|
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| Discussion|| |
Induction agent use has been found to reduce acute rejections in the early transplant period in several western studies.,, It allows a later start of calcineurin inhibitors, thus decreasing the risk of delayed graft function. In such studies, it has not been found to be associated with increased risk of infections or malignancy either. A meta-analysis in 2010 suggested that for a predominantly low immunologic risk transplant cohort: IL-2RB was effective in preventing rejection than no induction, ATG was not more effective than IL-2RB in preventing rejection, and IL-2RB had better safety profile than ATG. Because of all these reasons, it has become standard practice in the developed world to routinely use pretransplant induction therapy. However, these agents have not been shown to increase long-term survival with current standard immunosuppressive regimen consisting of Tac and MPA. Some studies have not shown any superiority of ATG over basiliximab in prevention of acute rejection or improving graft survival.,, There are no large randomized trials which have studied the effect of IL-2RB or ATG induction versus no induction in patients receiving the current standard maintenance immunosuppression, namely Tac, MPA, and steroids. Most of the available information in this regard is from retrospective studies. The realities of transplant practice are slightly different in developing countries. Infections predominate as the cause for mortality. Increased risk of infections and cost of therapy are two major factors that need to be considered in such settings, while thinking of using induction agents in kidney transplants.
In our study, we found that unadjusted long-term patient and graft survival were better in the induction group. There was reduction in acute rejections and interestingly a lower incidence of infections like TB and systemic fungal infections. The increase in graft survival is probably due to the decrease in rejections and the increase in patient survival due to reduction in life-threatening infections. The lower incidence of acute rejection episodes and therefore a lesser need for anti-rejection therapies resulted in lower net immunosuppression and consequently lesser incidence of serious infections leading to a better patient survival in the developing country scenario. In a Cochrane analysis of IL 2 receptor antagonists (IL2Ra) for KTRs, when IL-2Ra was compared with placebo (32 studies; 5784 patients), graft loss including death with a functioning graft was reduced by 25% at 6 months (16 studies: risk ratio [RR] 0.75, 95% confidence interval [CI] 0.58–0.98) and 1 year (24 studies: RR 0.75, 95% CI 0.62–0.90), but not beyond this. However, the observed better survival was attributable to the Tac-MPA regimen rather than the induction agent use as evident in the cox proportional hazards model. Given the preponderance of the Tac-MPA-based immunosuppressive regimen in the current transplants, we decided to analyze the outcomes of induction agent use among this selected group of patients. In those with Tac-MPA-based immunosuppression, there was no clear survival benefit with induction agent use. Given the increased potency of the Tac-MPA-based regime, this finding is not surprising. Nevertheless, even among the Tac-MPA group, induction agent use was associated with significant reduction in acute rejection, TB, and BK viremia. This assumes greater significance in the context of current understanding of the causative role of early acute rejections in the formation of donor-specific antibodies and later chronic rejection. Thus, even with Tac-MPA-based immunosuppression, use of induction therapy is beneficial, but not essential for all cases, especially for the low immunologic risk patients. This finding is in concurrence with other published studies. Lim et al. reported that IL-2 receptor antibody induction reduced rejections only in the intermediate risk recipients who received CsA-based regimen but not in low-risk transplants. Gralla and Wiseman performed a retrospective analysis of kidney transplants from 2000 to 2008 using US registry data, comparing patients who received triple immunosuppression consisting of prednisolone, Tac, and MPA with or without IL2RA induction and found a statistically significant reduction in 1-year acute rejection rate with induction (11.6% with IL2RA induction vs. 13.0% without induction) but no difference in patient or graft survival. Recently, Tanriover et al. conducted a large retrospective analysis of recipients of kidney transplants maintained on Tac, MPA, and prednisolone and found no benefit from use of IL-2 receptor blocker induction versus no induction in patients with respect to acute rejection or graft survival. In this analysis, ATG was associated with significantly lower rejections but did not improve graft survival.
Induction agents, by impairing early antigenic exposure to T cells and the consequent T cell help to B cells, not only reduce early rejection episodes but also help decrease de novo donor-specific antibody formation, and consequently chronic AMR and graft loss. This benefit is observed significantly in high immunologic risk transplant recipients, especially in those with previous sensitization. In addition, as the incidence of rejections declines, the number of methyl prednisolone pulse therapies and immunosuppression augmentation reduces, leading to lower cumulative immunosuppression, risk of infections, and improved patient survival.
We did not find any increased risk of infections with induction agent use irrespective of the immunologic risk group and even within the Tac-MPA group. This finding is of relevance since death with functioning graft is very high (as high as 88%) and infections have accounted for 36% of deaths in a study from India. This is in contrast to the developed world where rejection accounts for most of the graft loss. Thus, induction agent use could prove to be beneficial in terms of reducing rejection rates and consequently reduce infections irrespective of immunologic risk or baseline immunosuppression.
The economics of induction agent use is also very important in our and many other countries. ATG is about 30% cheaper than basiliximab in India, but there were concerns that it can predispose to serious infusion reactions, increased infections, and malignancies. In our study, given the effective use of CMV prophylaxis, the risk of CMV disease seems equivalent between the ATG and IL-2RB groups. There is however a higher incidence of BK viremia in ATG group that is important to note. There was no significant difference in survival (even within the high immunologic risk KTRs) between the ATG and IL-2RB group. However, ATG group had significantly better 1-year renal function. However, these findings have to be interpreted in the background of patient group characteristics. In high-risk patients, basiliximab was used more often in HLA AB nil match groups whereas ATG was used often in patients with previous crossmatch positivity. With the preferential ATG use in the relatively higher immunologic risk of crossmatch positivity, the patient and graft outcomes were comparable to those in basiliximab group of relatively lower immunologic risk of HLA nil matches. We did not observe any increased leukopenia with ATG use but incidence of NODAT appears to be raised with ATG. This is in contrast to other reports which showed increased diabetes mellitus associated with basiliximab use. Whether this observation is causal requires further research.
Limitations of the study
Being a retrospective study, the population is heterogeneous, and the numbers of patients in the comparison groups are not similar. The sample size and duration of follow-up may not be adequately powered to detect effects. There were also changes in the usual immunosuppression protocols over the years. Protocol biopsies were not done, and biopsies were done only for indication, which might have led to missing of subclinical rejections.
| Conclusions|| |
In developing countries like India, the use of induction agents (ATG/Basiliximab) is associated with benefits of reduced incidence of acute rejections and serious infection such as TB and BK viremia. The survival benefit of induction agent use is lost with the Tac-MPA-based immunosuppression. Thus, induction agent use is safe and beneficial but not essential for better survival if using the Tac-MPA-based immunosuppression in low immunologic risk LD-KT. Among high immunologic risk LD-KT, a selective strategy of using ATG predominantly for previously sensitized patients versus basiliximab for other lesser at-risk patients resulted in similar patient and graft survival. A selective approach of using induction agents based on risk profile can ensure a safe, successful, and cost-effective transplant program in economically challenged settings.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]