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Table of Contents
ORIGINAL ARTICLE
Year : 2022  |  Volume : 16  |  Issue : 1  |  Page : 113-118

Study of noninduction immunosuppression in intermediate-risk living donor kidney transplantation in rural population of India - A retrospective observational study


1 Department of Nephrology, MGM Medical College, Aurangabad, India
2 Department of Medicine, MVPS Dr Vasantrao Pawar Medical College and Research Center, Nashik, Maharashtra, India

Date of Submission07-Jul-2021
Date of Acceptance17-Oct-2021
Date of Web Publication31-Mar-2022

Correspondence Address:
Dr. Sudhir Gajanan Kulkarni
Department of Nephrology, MGM Medical College, N-6, CIDCO, Aurangabad - 431 003, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_70_21

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  Abstract 


Introduction: Kidney transplant is a costly affair, especially in a developing country like India. The current study was carried out with the aim to analyze the clinical outcome retrospectively in terms of acute rejection (AR), graft survival, and patient survival in intermediate-risk recipients undergoing first renal transplant with Tacrolimus (TAC), Mycophenolic acid (MPA), and corticosteroid based triple maintenance immunosuppression in one of the most underprivileged population of the country who has to bear the cost of the induction agent not covered by any government scheme. Materials and Methods: It is a retrospective observational study. We included 101 patients, out of which 42 were in basiliximab group and 59 patients did not receive any induction agent. Apart from the induction, agent rest of the Immunosuppression protocol was same in all patients. The primary endpoint of the study was number of biopsy-proven AR within 1st year of transplantation. The secondary endpoints were patient and graft survival by 1 year. Results: Human leukocyte antigen mismatch and mean age of the patients in basiliximab group were significantly higher than noninduction group; otherwise, both groups were similar in all other baseline parameters. There was no significant difference between AR (21.43% v/s 18.64%), graft survival (97.30% v/s 98.15%), and patient survival (88.10% v/s 91.52%) at 1 year. Conclusion: Our study suggests that Induction immunosuppression may not be necessary for patients undergoing intermediate-risk living donor kidney transplant in the current scenario of TAC and MPA-based maintenance immunosuppression.

Keywords: Basiliximab, induction, intermediate-risk, noninduction, renal transplant


How to cite this article:
Data A, Gadekar KG, Mogal VR, More AS, Kulkarni SG. Study of noninduction immunosuppression in intermediate-risk living donor kidney transplantation in rural population of India - A retrospective observational study. Indian J Transplant 2022;16:113-8

How to cite this URL:
Data A, Gadekar KG, Mogal VR, More AS, Kulkarni SG. Study of noninduction immunosuppression in intermediate-risk living donor kidney transplantation in rural population of India - A retrospective observational study. Indian J Transplant [serial online] 2022 [cited 2022 May 25];16:113-8. Available from: https://www.ijtonline.in/text.asp?2022/16/1/113/342442




  Introduction Top


Kidney transplant is a costly affair, especially in a developing country like India. Induction therapy increases the cost of transplantation in intermediate-risk individuals, more so in economically constrained populations in developing countries. The cost of an ABO compatible kidney transplant at our center is approximately INR 300,000/-which does not include induction immunosuppression. The cost of an immunosuppressive agent, either Interleukin-2 Receptor Antibody (IL2-RA) or anti-thymocyte globulin (ATG), adds substantially to the cost of the treatment.

Basiliximab is a monoclonal antibody against IL2 Receptors and is recommended in low-to-intermediate immunological risk renal transplants.[1] It was the only food and drug administration (FDA) approved induction agent in renal transplantation till 2017.[2] Other induction agent which is widely used around the world is rabbit Anti ATG (rATG), and is also approved by FDA in 2017. rATG is a lymphocyte depleting agent which has the capacity to deplete both B-cell and T-cell along with inhibition of B- and T-cell cooperation as well as leukocyte adhesion.[3]

Initially, the use of basiliximab was supported by clinical trials which reported the significantly lower rate of acute rejections (AR) when the maintenance immunosuppression included cyclosporine and azathioprine, but no trial demonstrated any improvement in the graft and patient survival when compared to placebo.[4],[5],[6] In the present scenario of triple immunosuppression for maintenance, which includes Tacrolimus, Mycophenolic Acid (TAC/MPA), and steroid, the role of IL2-RA as induction is debatable because the benefit of induction is lower than previously reported.[7],[8] With this triple maintenance therapy, the addition of induction may achieve an absolute risk reduction for AR of only 1%–4% in standard-risk patients without improving graft or patient survival.[9]

The current study was carried out retrospectively with the aim to analyze the clinical outcomes in terms of AR, graft survival, and patient survival in kidney recipients in one of the most underprivileged populations of the country who has to bear the cost of an induction agent not covered by any government scheme.


  Materials and Methods Top


Study participants

Our study is a retrospective observational study. We included all ABO compatible intermediate-risk living-related kidney transplant recipients admitted from January 2013 to December 2020 for transplant surgery in a tertiary care hospital. Inclusion criteria were the first transplant, and negative lymphocyte crossmatch. Panel reactive antibody and donor-specific antibody were not done because of financial reasons. Included patients were divided into two groups, the one who received basiliximab for induction and the other group who did not receive any induction agent. Patients with cadaveric donors and those who received rATG as induction were excluded from the study.

Study protocol

Our immunosuppression protocol was according to the Transplantation Society.[10] The patients who opted for basiliximab induction were given two doses of 20 mg diluted in 100 ml normal saline over 1 h on day 0 before surgery and on day 4. All patients were given injection Methylprednisolone 500 mg diluted in 100 ml normal saline intra-operatively and 125 mg 6 h after surgery. Tablet prednisolone 20 mg was given from day 1 to day 30 followed by 10 mg from day 31 to 90 and then decreased to 7.5 mg till 1 year. Tablet TAC was started one day prior with a dose of 0.06 mg/kg/dose twice daily in the noninduction group and at 0.05 mg/kg/dose twice daily in the basiliximab group. TAC levels were monitored to maintain trough levels of 5–8 ng/ml in the basiliximab group. In the noninduction group, TAC level was maintained 8–10 ng/ml in the first 60 days and level of 5–8 ng/ml after 60 days. TAC drug levels were monitored on 2nd and 7th day postoperatively and then as required depending on serum creatinine. Tab MPA was also started 1 day prior with a dose of 720 mg and continued 720 mg twice daily till 3 months after which it was decreased to 1080 mg per day in most of the patients.

Patients underwent graft kidney biopsy on suspicion of AR. All biopsy samples were processed for light Microscopy and C4d staining. The rejections were classified using the Banff criteria 2013 by the same pathologist. Patients were treated with IV Methylprednisolone 500 mg daily for three to 5 days in case of acute cellular rejection (ACR).[1] Patients with antibody-mediated rejection (AMR) were treated with Plasmapheresis 1.5 volumes and low-dose IV immunoglobulin 100 mg/kg on alternate days for 5 doses along with IV Methylprednisolone.[1] After discharge, patients were followed up for twice a week for initial 1 month, then every week for the next 2 months followed by every 2 weeks for another 3 months and then monthly till 1 year, and at each visit, kidney functions and complete blood counts were monitored.

The primary endpoint of the study was the number of biopsy-proven AR within 1st year of transplantation. The secondary endpoints were patient and graft survival by 1 year.

Statistical analysis

Data were entered into Microsoft Excel software. Data are reported as mean ± standard deviation and proportions when required. Chi-square test, Student's t-test, and Mann–Whitney U-test were used where required. P < 0.05 was considered statistically significant.

This study was approved by Institutional Review Board and Ethics Committee.

Patient consent

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.

Ethics statement

The study is approved by MGM ETHICS COMMITTEE FOR RESEARCH ON HUMAN SUBJECT with registration number EC/581/Inst/MH/2014/RR-20. Study carried out as per the declaration of Helsinki.


  Results Top


Basic demographics

Of the total of 108 live-related kidney transplant done at our center during the study, 47 recipients opted for induction immunosuppression, out of which 3 received rATG and 2 were lost to follow up hence excluded from the analysis. 61 recipients who did not opt for basiliximab and 2 patients were lost to follow-up. Hence, 42 patients in basiliximab and 59 patients in noninduction group were included in this study.

Majority of the recipients were males, out of total 101 recipients 93 were male and 8 were female [Table 1]. 95.24% and 89.83% of the recipients were males in basiliximab and noninduction groups respectively. The mean age of the population was 32.7 years with recipients in the basiliximab group significantly older than noninduction group. Donor age was statistically similar in both the groups with most of the donors were females in both the groups.
Table 1: Baseline demographics

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Baseline characteristics

Most of the (79.20%) recipients had native kidney disease of undetermined etiology, which is consistent with the younger population of recipients with 69.04% and 86.44% in basiliximab and noninduction group, respectively. The next common etiology was chronic Glomerulonephritis which was 16.67% in the induction group and 8.47% in the noninduction group. There were 2 patients with diabetes as etiology of chronic kidney disease (CKD) in the basiliximab group and none in the noninduction group. Human leukocyte antigen (HLA) Mismatch was significantly higher in the basiliximab group than noninduction group [Table 1].

Serum creatinine at the time of discharge in basiliximab and noninduction group was 1.17 ± 0.45 mg/dL and 1.22 ± 0.45 mg/dL respectively whereas at 1 year it was 1.43 mg/dL and 1.40 mg/dL, respectively. There was no statistical difference in serum creatinine value between both the groups at the time of discharge and at 1 year.

Acute rejections

A total of 9 (21.43%) recipients in the basiliximab group and 11 (18.64%) recipients in the noninduction group had AR by 1st year, and this was not statistically different [Table 2]. Fourteen rejections out of a total of 20 occurred in the 1st month, and rest occurred after 1 month, and this was also not statistically different when both the groups were compared. All rejections were categorized in the Banff category on the basis of Biopsy findings. Of the 11 rejections in noninduction group, 2 were AMR, whereas none had AMR in the basiliximab group. Basiliximab group and noninduction groups both had 5 recipients with ACR. Four recipients had borderline cellular rejections in both the groups.
Table 2: Acute rejections and banff categories

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Secondary endpoint

There were a total of 5 deaths by the end of 1 year in each of the groups. In the noninduction group, 4 out of 5 patients died of disseminated infections and 1 patient died at home, the cause could not be identified. In the basiliximab group, 4 patients died of disseminated infection, and 1 patient died of intracerebral bleeding. Out of surviving recipients, there was only 1 recipient who had severe graft dysfunction and needed to start hemodialysis in each group [Table 3].
Table 3: Graft and patient survival

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  Discussion Top


KDIGO 2009 guidelines recommend the use of IL2-RA as the first-line induction therapy and suggest the use of a lymphocyte depleting agent for high immunologic risk kidney transplant recipients.[1] The transplantation society protocol, for intermediate-risk recipients, recommends use of IL2-RA with TAC of 0.05 mg/kg to maintain the trough level of TAC to 5–8 ng/ml whereas dose of 0.06 mg/kg without IL2-RA to maintain level of 8–10 ng/ml.[10]

We retrospectively studied 101 live related intermediate-to-high immunological risk kidney transplant recipients for incidence of AR at the end of 1st year and compared between the patients who received basiliximab as induction Immunosuppression and patients who did not receive induction agent. All recipients received injection Methylprednisolone 500 mg intra-operatively and 125 mg 6 h after surgery along with triple immunosuppression-based regimen including TAC, MPA, and Prednisolone for maintenance.

The current study had the majority of the males as recipients (92%) and the majority of the donors as females (79%). This is in accordance with the scenario found in other Indian studies.[11],[12] However, recipients were younger; however, donors were comparatively older in the current study.[11],[12] Younger age of recipients was due to the majority of patients having CKDu as the cause of CKD in each group and only 2 patients had diabetes as the cause in the induction group. A study from North India by Bansal et al. also had CKDu as the major cause but in contrast to the current study, they had a substantial proportion of recipients with diabetic nephropathy.[11] We found the significant difference with respect to age and HLA mismatch of the recipients between the two groups. This is because the donors in the basiliximab group were unrelated.

Our study showed the incidence of AR by the end of 1 year to be 21.43% in the basiliximab group and 18.64% in the noninduction group. Most of the rejections in both the groups occurred within the 1st month, which is also similar to finding in other studies.[11],[12] It is worth noting that there was no AMR in the basiliximab group and 2 patients had AMR in the noninduction group. We did not observe a high rate of AMR due to intermediate-risk recipients. A high rate of ACR within the first 30 days remains unexplained; however, such high incidence was also reported by Bansal et al. in their study.[11] The patient survival and graft survival were also statistically similar in both the groups.

It is still a debatable issue whether there is a need of an induction agent in intermediate-risk live-related kidney transplant. rATG and basiliximab showed a reduction in incidence for ARs initially when compared to recipients who did not receive any induction although there was no benefit in patient and graft survival. This benefit was mainly seen in population receiving cyclosporine-based regimen, and this benefit faded with the advent of TAC-based triple immunosuppression for maintenance.[6],[9]

In 2010, a Cochrane systematic review compared the effect of IL2-RA to placebo and included 32 studies with 5854 patients. They found a 25% reduction in graft loss at the end of 6 months and 1 year along with 28% reduction in biopsy-proven AR. The authors concluded that compared with no induction treatment one would need to treat nine recipients with IL2-RA to prevent one recipient having rejection and 42 recipients to prevent one graft loss.[13] However, the review mainly included studies with cyclosporine-based maintenance Immunosuppression, only 2 studies were there which included patients with TAC-based regimen.[13]

Two more studies were published in 2010, from large registry data, comparing benefits of IL2-RA with no induction by Lim et al. and Gralla and Wiseman former study examined renal transplant recipients from Australia and New Zealand and Transplant Registry between 1995 and 2005. They found that the benefit of IL2-RA was restricted to cyclosporine-treated patients but not in TAC-treated patients, and IL2-RA did not show any benefit when compared with no induction in patients with ≤2 HLA mismatch with Panel Reactive Antibody <10%.[6] The latter study by Gralla and Wiseman retrospectively analyzed primary kidney transplant recipients from Scientific Renal Transplant Registry from 2000 to 2008. They included 28,686 patients with initial Immunosuppression of TAC, MPA, and prednisone. They found a minimal but statistically significant reduction in the incidence of AR with IL2-RA but no reduction in graft or patients' survival at the end of 1st and 3rd year. The authors finally concluded that a significant reduction in AR rates concurrent with TAC/MPA-based triple Immunosuppression may reduce the utility of IL2-RA induction. Unlike the previous review, 70 patients would need to be treated to prevent one episode of AR overall, and at least 53 patients would need treatment to prevent one episode of AR in recipients of living donor kidney transplant. It is also worth noting that both of these large studies had the majority of recipients who received kidneys from deceased donors.[7]

Gundlapalli et al. published an observational study from North India in 2013. 46 patients on basiliximab induction were compared to risk-matched 56 controls at the end of 6-and 12-months posttransplant. They found that recipients in the basiliximab group had to bear an additional cost of Rs 100,000/patient as compared to no induction group. The incidence of biopsy-proven AR was similar in both the groups at the end of 6 and 12 months (12.5% v/s 13% at 6 months and 20.5% v/s 18.9% at 12 months. And also, there was no difference in death censored graft survival at the end of 1st year post transplant between the groups. However, this study included patients who underwent first transplant from July 2009 to June 2011 from spousal or unrelated or poorly matched related donors.[12]

In 2015 Tanriover et al. published a study on patients from The Organ Procurement and Transplantation Registry who underwent living donor renal transplant from 2000 to 2012 and were maintained on TAC and MPA on discharge. They included 36,153 patients and initially divided patients into 2 groups based on the use of steroids in maintenance immunosuppression. The steroid group was further divided into three subgroups on the basis of the induction approach: IL2-RA, rATG, and no induction. It was found that there was no significant difference in relative risk of AR between IL2-RA and no induction groups, but the risk for AR was significantly lower in rATG group when compared with the IL2-RA group. However, the hazard ratios for overall allograft failure were not significantly different between the rATG and no induction group when compared with the IL2-RA category. The authors concluded that considering adverse effects and cost, no induction therapy is a reasonable option in concerned population and that it is a plausible strategy to limit the use of rATG to patients at increased risk for AR to keep a favorable balance between benefits and serious adverse effects.[8]

Another Indian study by Bansal et al. compared the benefit of basiliximab with no induction in first kidney recipients of living donor with TAC and Mycophenolate Mofetil-based triple maintenance Immunosuppression. They included 202 patients in Basiliximab group and 58 patients in no induction group and observed that there was no difference in the incidence of biopsy-proven AR (20.8% v/s 17.2%), graft survival (97% v/s 98.3%), and patient survival (99% v/s 98.2%). They concluded that there is no advantage of using basiliximab in reducing AR in first kidney recipients of living donors in TAC-based triple immunosuppression.[11]

Radhakrishnan et al. analyzed the outcome of living donor kidney transplant recipients for ARs, patient, and graft survival. They divided the population into induction and no induction group. The induction group was further categorized into those who received basiliximab and those who received ATG. They observed that there was reduction in ARs, and it just reached significance (18.9% v/s 26.3%) with better patient and graft survival when the induction group was compared to the no induction group. In the low immunological risk group, there was better overall patient survival, but there was no difference in graft survival and ARs; however, among patients who received TAC-based regimen, there was no difference in patient survival also. In this study, they studied ATG also and when compared to IL2-RA, ATG did not show any benefit with respect to patient survival, graft survival, and ARs in both high and low immunological groups. It was concluded that in those with TAC and MPA-based immunosuppression, there was no clear survival benefit with any induction agent use and although the incidence of AR was lesser in induction group this might not hold true for low immunological risk recipients.[14]

Two more studies from Iran, published in 2019, compared the benefit of ATG with no induction. Shahbazian et al. conducted a randomized double-blind clinical trial and included 106 patients, 53 in each group. They did not find any difference in AR and graft survival. In this study, recipients with deceased donors were also included, and no significant difference of AR in recipients from deceased and living donor was detected.[15] Marghoob et al. retrospectively analyzed benefits of ATG in low-risk live-donor kidney transplant recipients. They included 114 patients, out of which 77 received ATG and 37 did not. 500 mg pulse therapy with Methylprednisolone was given for 3 days in both the groups. They also did not report any significant difference between the 2 groups in AR incidence (11.7% in ATG v/s 10.8% in the control group). In this study, majority of the patients received TAC-based immunosuppression with 94.8% in ATG group and 89.18% in the control group.[16]

Limitations

Our study has limitations in certain aspects as it is a single-center study with small sample size, and also this study being retrospective, nonrandomized study so selection bias is possible. The follow-up period was also short and long-term follow-up is required. However, the current study is the first report from the rural part of Maharashtra.


  Conclusion Top


Induction Immunosuppression may not be necessary for patients undergoing intermediate-risk living donor kidney transplant in the current scenario of TAC and MPA-based maintenance Immunosuppression. Noninduction treatment is acceptable, especially in a financially constrained population who cannot undergo transplant because of a shortage of funds. This will make kidney transplant acceptable to a wider population. However, a study with a longer than 1-year follow-up with more number of patients is required to draw a definite conclusion.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009;9 Suppl 3:S1-155.  Back to cited text no. 1
    
2.
Hardinger KL, Brennan DC, Klein CL. Selection of induction therapy in kidney transplantation. Transpl Int 2013;26:662-72.  Back to cited text no. 2
    
3.
Bamoulid J, Staeck O, Crépin T, Halleck F, Saas P, Brakemeier S, et al. Anti-thymocyte globulins in kidney transplantation: Focus on current indications and long-term immunological side effects. Nephrol Dial Transplant 2017;32:1601-8.  Back to cited text no. 3
    
4.
Kahan BD, Rajagopalan PR, Hall M. Reduction of the occurrence of acute cellular rejection among renal allograft recipients treated with basiliximab, a chimeric anti-interleukin-2-receptor monoclonal antibody. United States Simulect Renal Study Group. Transplantation 1999;67:276-84.  Back to cited text no. 4
    
5.
Adu D, Cockwell P, Ives NJ, Shaw J, Wheatley K. Interleukin-2 receptor monoclonal antibodies in renal transplantation: Meta-analysis of randomised trials. BMJ 2003;326:789.  Back to cited text no. 5
    
6.
Lim WH, Chadban SJ, Campbell S, Dent H, Russ GR, McDonald SP. Interleukin-2 receptor antibody does not reduce rejection risk in low immunological risk or tacrolimus-treated intermediate immunological risk renal transplant recipients. Nephrology (Carlton) 2010;15:368-76.  Back to cited text no. 6
    
7.
Gralla J, Wiseman AC. The impact of IL2ra induction therapy in kidney transplantation using tacrolimus- and mycophenolate-based immunosuppression. Transplantation 2010;90:639-44.  Back to cited text no. 7
    
8.
Tanriover B, Zhang S, MacConmara M, Gao A, Sandikci B, Ayvaci MU, et al. Induction therapies in live donor kidney transplantation on tacrolimus and mycophenolate with or without steroid maintenance. Clin J Am Soc Nephrol 2015;10:1041-9.  Back to cited text no. 8
    
9.
Hellemans R, Bosmans JL, Abramowicz D. Induction therapy for kidney transplant recipients: Do we still need anti-IL2 receptor monoclonal antibodies? Am J Transplant 2017;17:22-7.  Back to cited text no. 9
    
10.
Eckberg H, Qi Z. Practical protocol for living kidney donor transplant. The Transplantation Society; 2010. Available from: https://www.tts.org/images/stories/practical_protocols/Practical_Protocols_ENG.PDF. [Last accessed on 2021 May 01].  Back to cited text no. 10
    
11.
Bansal SB, Pathania D, Sethi SK, Jha PK, Nandwani A, Jain M, et al. Basiliximab induction in living donor kidney transplant with tacrolimus-based triple immunosuppression. Indian J Transplant 2019;13:104-9.  Back to cited text no. 11
  [Full text]  
12.
Gundlapalli S, Rathi M, Kohli HS, Jha V, Sharma A, Minz M, et al. Efficacy of basiliximab induction in poorly matched living donor renal transplantation. Indian J Nephrol 2013;23:409-12.  Back to cited text no. 12
[PUBMED]  [Full text]  
13.
Webster AC, Ruster LP, McGee R, Matheson SL, Higgins GY, Willis NS, et al. Interleukin 2 receptor antagonists for kidney transplant recipients. Cochrane Database Syst Rev 2010;(1):CD003897.  Back to cited text no. 13
    
14.
Radhakrishnan RC, Basu G, Mohapatra A, Alexander S, Valson AT, Jacob S, et al. Utility of induction agents in living donor kidney transplantation. Indian J Transplant 2019;13:202-9.  Back to cited text no. 14
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15.
Shahbazian H, Ghorbani A, Hayati F, Beladi Mousavi SS, Sabetnia L, Ahmadi Halili S, et al. Comparison of clinical outcome of induction immunosuppressive therapy with thymoglobulin and standard therapy in kidney transplantation; a randomized double-blind clinical trial. J Nephropathol 2020;9:e08.  Back to cited text no. 15
    
16.
Marghoob B, Rahimian N, Ataiepour Y, Mahdifarani M, Nejatifar M, Kabir A. Comparing the effect of induction therapy with or without antithymocyte globulin on renal allograft outcomes in live-donor kidney transplant recipients. Med J Islam Repub Iran 2019;33:141.  Back to cited text no. 16
    



 
 
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