|Year : 2022 | Volume
| Issue : 2 | Page : 166-173
Outcomes in live renal allograft transplants with different modalities of induction: A hospital-based retrospective study in Odisha
Datteswar Hota1, Sucharita Chakraborty2, Kumar Avijeet Dash2, Chittaranjan Kar2, Shashi Bhusan Rout2, Aruna Acharya2, Debasish Mahali1
1 Department of Urology and Renal Transplantation, SCB Medical College and Hospital, Cuttack, Odisha, India
2 Department of Nephrology and Renal Transplantation, SCB Medical College and Hospital, Cuttack, Odisha, India
|Date of Submission||06-Jan-2021|
|Date of Acceptance||03-Jun-2021|
|Date of Web Publication||30-Jun-2022|
Dr. Sucharita Chakraborty
Department of Nephrology and Renal Transplantation, SCB Medical College and Hospital, Cuttack, Odisha
Source of Support: None, Conflict of Interest: None
Introduction: The immunosuppressant regimen after kidney transplantation typically includes initial induction therapy followed by a maintenance regimen. The induction therapy was introduced with the aim of reducing acute rejections. A retrospective study was conducted to compare the outcomes in patients with different modalities of induction. Materials and Methods: This is a hospital-based retrospective study where 148 patients who have undergone live renal allograft transplantation at SCB Medical College and Hospital from March 2012 to February 2019 were included in the study. All cases included were crossmatch negative, ABO-compatible live renal allograft transplantations. All patients received tacrolimus, mycophenolate sodium, and steroids. Induction therapy varied depending on immunological risk and changes in protocol over time. Basiliximab, anti-T-lymphocyte globulin (ATLG), and anti-thymocyte globulin (ATG) were given in 56, 21, and 21 patients, respectively, and no induction therapy in 50 patients. All patients with an acute rise in serum creatinine and without an obvious cause of graft dysfunction were subjected to renal biopsy. The incidence of acute rejection, patient survival, and graft survival was calculated from the follow-up records and compared among patients receiving different induction therapies. Results: In the high-risk category patients, 31%, 20%, and 18.2% of patients (P = 0.6) and in the low risk category, 37%, 27.3%, and 20% of patients (P = 0.6) had acute rejections in basiliximab, ATLG, and ATG group, respectively. The patient survival at 1 year was 79.3%, 70%, and 81.8% in high-risk group patients (P = 0.84) and 88.9%, 81.8%, and 80% in low-risk group patients (P = 0.88) in the basiliximab, ATLG, and ATG groups, respectively. The graft survival at 2 years was 96.6%, 90%, and 90.9% in high-risk group patients (P = 0.32) and 88.9%, 90.9%, and 90% in low-risk group patients (P = 0.65) in the basiliximab, ATLG, and ATG groups, respectively. Conclusion: In the low-risk group, the use of different modalities of induction does not have any advantage over no induction therapy in reducing the incidence of acute rejection, or improving patient and graft survival. In the high-risk group, all the induction therapies used lead to similar outcomes and none show any advantage over the other in terms of statistical significance. However, patients who received ATLG or ATG have an increased incidence of septicemia as compared to basiliximab and no induction group.
Keywords: Anti-thymocyte globulin, anti-T-lymphocyte globulin, basiliximab, induction, kidney transplantation, rejection, survival
|How to cite this article:|
Hota D, Chakraborty S, Dash KA, Kar C, Rout SB, Acharya A, Mahali D. Outcomes in live renal allograft transplants with different modalities of induction: A hospital-based retrospective study in Odisha. Indian J Transplant 2022;16:166-73
|How to cite this URL:|
Hota D, Chakraborty S, Dash KA, Kar C, Rout SB, Acharya A, Mahali D. Outcomes in live renal allograft transplants with different modalities of induction: A hospital-based retrospective study in Odisha. Indian J Transplant [serial online] 2022 [cited 2022 Aug 15];16:166-73. Available from: https://www.ijtonline.in/text.asp?2022/16/2/166/349346
| Introduction|| |
Chronic kidney disease is estimated to affect about 11%–13% of the population worldwide. Kidney transplantation remains the treatment of choice for end-stage renal disease as it leads to longer survival and superior quality of life.
Acute graft rejection is one of the major confounders of renal transplantation. It is defined as a decline in renal function caused by an immune reaction against the allograft.
Major renal transplant centers have their own immunosuppressant protocol. The greatest source of intraprogram variability in an immunosuppressive regimen is the choice of induction therapy and patient selection for the same. Induction therapy is considered in patients at high risk of acute allograft rejection, for example, recipients with a history of multiple blood transfusions, spouse donor transplantations, donor with a history of multiple pregnancies, and ABO-incompatible transplantations. However, many centers opt for induction therapy in all patients undergoing transplantation to reduce the risk of allograft rejection.
The immunosuppressant regimen after kidney transplantation typically includes initial induction therapy followed by a maintenance immunosuppressant regimen.
Currently, lymphocyte-depleting agents (most frequently rabbit-anti-thymocyte globulin [rATG]) or IL2RA (basiliximab) induction is being used in most of the transplantation centers.
There are several formulations of polyclonal antilymphocyte sera available in different countries, generated in animals (rabbits, horses). Available rabbit polyclonal antilymphocyte sera are the ATG (Sanofi Genzyme, Cambridge, MA, USA), derived from rabbit vaccination with human thymocytes, and the anti-T-lymphocyte globulin (ATLG) (Grafalon, formerly ATG Fresenius®), derived from the human Jurkat T-cell line. The third formulation is Horse ATG (hATG, ATGAM®, Pfizer Inc., NY, USA).
The literature for comparison between the different induction agents is scarce in India as well as worldwide as most of the institutions use a single induction agent in all patients with indications for the same or different induction agents depending on the patients' baseline risk category. In our institution, the use of induction agent changed with time as our protocol for the same changed. Hence, there were institutional records on the use of different induction agents on patients with similar baseline characteristics. Therefore, we decided to undertake a retrospective study to compare the outcomes in our patients who received different induction agents.
| Materials and Methods|| |
This hospital-based retrospective study was conducted at SCB Medical College and Hospital (SCBMCH), a tertiary care Government Medical College and Hospital in Odisha.
All patients who underwent live-related, ABO-compatible, renal allograft transplantation from March 2012 to February 2019 at SCBMCH were included in the study with a minimum follow-up period of 1 month.
All patients who underwent renal allograft transplantation after January 2019 at SCBMCH, were excluded from the study.
This study was approved by the SCBMCH Institutional Ethics Committee. Live-related renal allograft transplantation started at SCBMCH in March 2012. The records of all patients who have undergone kidney transplantation up till January 2019 were analyzed. All cases were crossmatch negative, ABO-compatible live-related renal transplantations.
Immunosuppressives were started a day before transplantation. All patients received tacrolimus 0.1 mg/kg/day in two divided doses and the tacrolimus trough level was maintained at 8–12 ng/ml (first 3 months), 5–8 ng/ml (next 3 months), and 3–5 ng/ml thereafter. Mycophenolate sodium was started at 720 mg twice daily that was tapered to 720 mg per day after 6 months. All patients received intravenous (IV) methylprednisolone 500 mg intraoperatively. Oral prednisolone was started at 20 mg/day, then tapered off to 5 mg/day by the end of 6 months. Induction therapy with basiliximab (20 mg each on day 0 and day 4) or ATG or ATLG (1.5 mg/kg on days-1, 0 and 2) was given mostly in high-risk groups (second transplant, spousal transplants). The choice of induction agent was as per the hospital protocol being followed at the time of transplantation.
Graft dysfunction was defined as a rise in serum creatinine by 25% above the baseline. Without an obvious cause of graft dysfunction, all patients with an acute rise in creatinine were subjected to renal biopsy.
The rejections were classified according to the Banff classification criteria (2017). All acute cell-mediated rejections were treated with IV methylprednisolone 500 mg/day for 5 days. The steroid-resistant cases were treated with IV ATG 1.5 mg/kg on alternate days (3 doses). The acute antibody-mediated rejections were treated with plasmapheresis 40 ml/kg volume exchange (3–5 sessions) and IV immunoglobulin 100 mg/kg on alternate days.
The incidence of acute rejection, patient survival, and graft survival was calculated from the follow-up records of all patients and the modalities of induction they received were recorded. The outcomes in patients receiving different modalities of induction therapies were compared. The clinical, biochemical, and pathological records (renal biopsy reports) of such patients were analyzed to determine the type of rejection. Informed consent from all the patients who underwent live-related renal allograft transplantation during the study period was obtained.
The data collected were entered into Microsoft Excel worksheet and analyzed using Statistical Package for Social Sciences, version 15.0 (SPSS Inc., Chicago, IL, USA). Normally distributed continuous variables were expressed as mean and standard deviation, and categorical variables were expressed as proportions. Parametric statistics involving one-way analysis of variance was employed to compare continuous variables. Chi-square or Fischer's exact statistics with odds ratio and 95% confidence intervals were assessed for association among categorical variables. The significance of the difference in cumulative survival proportions in terms of grafts and patients was performed by Kaplan–Meier estimator with log-rank (Mantel–Cox) Chi-square statistics. P < 0.05 was considered significant for all statistical inferences.
The patient consent has been taken for participation in the study and for publication of clinical details and images. Patients understand that the names and initials would not be published, and all standard protocols will be followed to conceal their identity.
Study was approved by Institutional Ethical Committee, SCB Medical College and Hospital, Cuttack, Odisha, IEC/Appln No. 99. All guidelines of Declaration of Helsinki were folllowed. The study was performed according to the guidelines in Declaration of Helsinki.
| Results|| |
A total of 148 patients underwent renal transplantation during the study period considered and all these patients were included in the study. All the patients have either regularly followed up or were tracked successfully to attain the information needed for the study. Fifty patients (33.8%) have not received any induction therapy. Among the rest, 56 (37.8%), 21 (14.2%), and 21 (14.2%) patients have received induction with basiliximab, ATLG, and ATG respectively. Among all, 98 (66.2%) patients were of low-risk category and 50 (33.8%) patients were of the high-risk category. All patients who did not receive any induction were of the low-risk category, but some patients of the low-risk category did receive induction therapy as our hospital protocol changed to “induction in all patients” during the given time.
The mean age of patients was 31.04 ± 7.4, 35.7 ± 9.65, 34.73 ± 9.85, and 32.5 ± 5.96 years in low-risk category patients (P = 0.11) in the no induction, basiliximab, ATLG, and ATG groups, respectively. The mean age of patients was 42.62 ± 7.83, 40.7 ± 12.17, and 38.82 ± 10.62 years in high-risk category patients (P = 0.5) in the basiliximab, ATLG, and ATG group, respectively. The age of donors also was similar in the high-risk category (P = 0.19) and in the low-risk category (P = 0.06) among the different induction group patients [Table 1] and [Figure 1]. The gender distribution of patients as well as the donors among the different groups in both the categories also was similar [Table 2] and [Figure 2]. The human leukocyte antigen (HLA) mismatches in the high-risk group and the low-risk group patients among basiliximab, ATLG, and ATG groups were similar.
|Table 1: Mean age of recipients and donors in low-risk and high-risk category patients|
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|Figure 1: Distribution of mean age of donors and recipients in high- and low-risk categories among different modalities of induction therapies|
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|Table 2: Gender distribution of recipients and donors in low-risk and high-risk category patients|
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|Figure 2: Frequency distribution of gender of donors and recipients in high- and low-risk categories among different modalities of induction therapies|
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A total of 32 (21.6%) patients had biopsy-proven acute rejections (BPAR) within the first 6 months and the rest 9 (6.2%) patients had thereafter. BPARs occurred in 9 (31.1%), 2 (20%), and 2 (18.2%) in the basiliximab, ATLG, and ATG groups, respectively, in the high-risk category patients with P = 0.6. Similarly, when only the low-risk group patients were considered, the incidence of BPARs was not significantly different in various groups with P = 0.6. The types of rejections that occurred in patients receiving different induction agents are mentioned in [Table 3] and depicted in [Figure 3].
|Table 3: Types of rejections occurring in patients receiving different modalities of induction therapy|
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|Figure 3: Types of rejections occurring in patients receiving different modalities of induction therapies|
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The number of patients who survived in the high-risk category till 1 year post transplant was 23 (79.3%), 7 (70%), and 9 (81.8%) in the basiliximab, ATLG, and ATG groups, respectively with P = 0.84. In addition, when compared among different groups in the low-risk category patients, the patient survival at 1 year was 41 (82%), 24 (88.9%), 9 (81.8%), and 8 (80%) in the no induction, basiliximab, ATLG, and ATG groups, respectively, (P = 0.88). The causes of death in patients receiving different modalities of induction are mentioned in [Table 4] and depicted in [Figure 4].
Death-censored graft survival
In the high-risk patients, 1 graft loss occurred within 2 years post transplant in each of the induction groups. The death-censored graft survival at 2 years in these patients was 96.6%, 90%, and 90.9% in the basiliximab, ATLG, and ATG groups, respectively. There were 5, 3, 1, and 1 graft losses within 2 years of transplant surgery in the no induction, basiliximab, ATLG, and ATG groups, respectively of the low-risk category. The death-censored graft survival at 2 years was hence calculated and was 90%, 88.9%, 90.9%, and 90% in the no induction, basiliximab, ATLG, and ATG groups, respectively.
The significance of the difference in cumulative survival proportions in terms of patients [high risk = [Table 5] and [Figure 5]] [low risk = [Table 6] and [Figure 6]] and grafts [high risk = [Table 7] and [Figure 7]] [low risk = [Table 8] and [Figure 8]] was examined by Kaplan–Meier analysis employing log-rank (Mantel–Cox) Chi-square statistics among four treatment groups. No statistically significant difference in survival proportion among treatment groups was observed.
|Figure 5: Kaplan–Meier survival curves to compare patient survival in high-risk category patients|
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|Figure 6: Kaplan–Meier survival curves to compare patient survival in low-risk category patients|
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|Figure 7: Kaplan–Meier survival curves to compare graft survival in high-risk category patients|
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|Figure 8: Kaplan–Meier survival curves to compare graft survival in low-risk category patients|
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Some specific complications attributable to immunosuppression were recorded. Among all patients, 41 (31.1%) patients had sepsis, 8 (5.4%) had BK virus infection, 7 (4.7%) had tuberculosis, and 9 (6.1%) had posttransplantation diabetes mellitus. The incidence of septicemia was compared among patients receiving different induction therapies and no induction [Table 9]. It was noted to be significantly higher in the ATLG and ATG group as compared to the basiliximab and no induction group with P < 0.001.
|Table 9: Comparison of incidence of sepsis among individual induction modalities|
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| Discussion|| |
As there is a paucity of data regarding the comparison of outcomes among various induction agents in Eastern India, this study was carried out to know and compare the outcomes among renal allograft recipients receiving different modalities of induction therapy.
Among all recipients, the total incidence of rejection was 27.7%, the patient survival at 1 year was 81.1%, and the death-censored graft survival at 2 years was 93.23%.
Multiple trials have demonstrated the role of induction therapy with ATG or IL2RA induction in reducing the risk of acute rejection episodes after kidney transplantation. The Cochrane Collaboration published a meta-analysis of randomized controlled trials in 2010 that compared IL2RA induction with placebo and ATG. BPAR rates were 30% lower with IL2RA versus placebo and graft loss was reduced. It consisted primarily of recipients at low immunological risk. ATG was no more effective in preventing rejection than IL2RA agents, and the safety profile favored IL2RA induction. The Cochrane meta-analysis, which formed the basis of the current KDIGO recommendations, included studies that were conducted mostly in the 1990s and early 2000s using maintenance regimens that have since been changed.
Similarly in our study, when all patients irrespective of the risk category were considered, the highest incidence of acute rejection was seen in the patients who received basiliximab (9 patients; 33.9%) and lower in the patients who received ATG (4 patients; 19%) and ATLG (5 patients; 23.8%), but this difference was statistically insignificant (P = 0.552). The safety profile favored basiliximab, as shown in previous studies. Septicemia occurred more in patients receiving ATLG (14 patients; 66.6%) and ATG (13 patients; 61.9%) as compared to groups receiving basiliximab (11 patients; 19.6%) or no induction (8 patients; 16%) and the difference was statistically significant (P < 0.001).
Gralla and Wiseman did a retrospective analysis using U. S. registry data from primary kidney transplants performed during 2000–2008. This compared patients who received triple immunosuppressants consisting of tacrolimus, mycophenolic acid (MPA), and prednisone with or without IL2RA induction. The 1-year acute rejection rate was 11.6% with IL2RA induction versus 13.0% with no induction. Although statistically significant, the clinical relevance of the difference is questionable, particularly because IL2RA induction did not improve graft or patient survival.
In our study, all patients were on triple immunosuppressants consisting of tacrolimus, mycophenolate sodium, and steroids. Although statistically insignificant, the lower incidence of acute rejection in the no induction group as compared to the basiliximab group probably can be attributed to the fact that mostly lower risk patients with lower HLA mismatches and no complications received no induction as compared to basiliximab in our study.
Willoughby et al., a retrospective study, compared outcomes between kidney transplant patients who received ATG (Thymoglobulin), basiliximab, or no induction. ATG was associated with statistically superior outcomes with respect to the composite triple endpoint of allograft rejection, graft failure, or patient death compared with basiliximab, and both the agents were superior to no induction. The 6-month rejection rates were 13% without any induction, 11% with IL2RA, and 9% with ATG, with no impact on graft or patient survival.
In our study as well, the difference in patient survival at 1 year and death-censored graft survival at 2 years among patients receiving no induction, basiliximab, ATLG, and ATG was statistically insignificant in high- as well as low-risk category patients.
Tanriover et al. retrospectively analyzed U. S. registry data from patients who underwent living donor transplantation between 2000 and 2012 and who received tacrolimus, MPA, and steroids. In this population, IL2RA induction was not associated with any improvement in outcomes compared with no induction (acute rejection at 1 year 11.7% vs. 12.4% [P = 0.55]; similar graft survival at 5 years [P = 0.92]).
Data from the Australia and New Zealand Dialysis and Transplant Registry on renal transplant recipients between 1995 and 2005 also showed no reduction in rejection risk with IL2RA either in low-risk recipients or in tacrolimus-treated patients with intermediate immunological risk.
Similarly, in our study in the low-risk category patients, basiliximab group and no induction group had a similar incidence of rejection, patient survival at 1 year, and death-censored graft survival at 2 years with no significant variation.
The advantage of induction therapy appears to be more clear cut in high-risk kidney transplant recipients. KDIGO defined high immunological risk as to the following conditions: high number of HLA mismatches, younger recipient age, older donor age, African American ethnicity (in the United States), panel reactive antibodies >30%, presence of a donor-specific antibody, blood group incompatibility, delayed onset of graft function, and cold ischemia time >24 h.
Only two large randomized trials have compared IL2RA versus rATG induction specifically in this setting. Brennan et al. enrolled 278 patients at high risk of delayed graft function and/or acute rejection. Maintenance therapy consisted of cyclosporine, MPA, and steroids. The rejection rates were almost halved in high-risk patients given ATG versus IL2RA at 1 year (16% vs. 26%, P = 0.02) and at 5 years (15% vs. 27%, P = 0.03).
Noël et al. recruited 227 patients at high immunological risk. Maintenance therapy comprised tacrolimus, MPA, and steroids. Again, both the incidence and severity of acute rejection were significantly lower with rATG versus IL2RA. The acute rejection rate at 1 year was 15% versus 27% (P = 0.016), a difference that was maintained at 5-year follow-up (14% vs. 26%, P = 0.035). The results of these two studies led to the 2009 KDIGO recommendation to use lymphocyte-depleting induction in patients at high immunological risk. However, both the studies failed to show a difference in long-term graft or patient survival benefit with rATG compared with IL2RA.
In our study, the total number of high-risk transplants was 50. The age distribution, gender distribution, and degree of HLA mismatch in the three groups receiving basiliximab, ATLG, and ATG as their induction therapies were similar.
The incidence of rejection was 31%, 20%, and 18.2% in the basiliximab, ATLG, and ATG group, respectively. Although the lowest incidence of rejection is seen in the patients who received induction with ATG, this difference is statistically insignificant (P = 0.632).
The patient survival at 1 year was 81.8%, 79.3%, and 70% in patients who received induction with ATG, basiliximab, and ATLG, respectively. However, the difference was statistically insignificant (P = 0.781).
The death-censored graft survival at 2 years was 90.9%, 96.6%, and 90% in patients who received induction with ATG, basiliximab, and ATLG, respectively. However, the difference was statistically insignificant.
Hence although in the high-risk category, patients in the ATG group had the lowest incidence of rejection, better patient survival at 1 year and patients in the ATLG group had better death-censored graft survival at 2 years as compared to basiliximab, the difference between the groups was statistically insignificant.
The strength of our study is that we could compare outcomes in patients receiving three different modalities of induction as well as those who did not receive induction therapy in the same study population. However, there are several limitations in our study, First, it is a retrospective study with a small study population. Second, the protocol regarding the choice of induction therapy as well as indications of receiving induction therapy changed midway during the study period considered. Third, the size of the different treatment groups was unequal. Fourth, some low-risk patients also received induction therapies; hence, this has to be considered while comparing results in patients of different groups irrespective of their patients were similar.
| Conclusion|| |
In low-risk patients, the use of different modalities of induction does not have any advantage over no induction therapy in reducing the incidence of BPARs, or improving patient survival at 1 year and death-censored graft survival at 2 years. In the high-risk category patients as well, the difference between outcomes was not statistically significant among patients receiving different induction agents. However, septicemia occurred more in patients receiving induction with ATG and ATLG when compared to those receiving basiliximab or no induction.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9]