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Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 15  |  Issue : 1  |  Page : 50-55

Graft and survival outcome in renal transplant patients receiving cyclosporine and azathioprine versus tacrolimus and mycophenolate mofetil: A single-center retrospective observational study


Department of Nephrology, St. John's Medical College, Bengaluru, Karnataka, India

Date of Submission16-Apr-2020
Date of Acceptance05-Aug-2020
Date of Web Publication31-Mar-2021

Correspondence Address:
Dr. Limesh Marisiddappa
Department of Nephrology, St. John's Medical College, Bengaluru, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_33_20

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  Abstract 


There is paucity of data on long-term outcome of renal transplantation across different immunosuppression groups. Rationale and Objective: The study looks at long-term outcomes in renal transplant patients receiving azathioprine, cyclosporine combination (Group 1) with mycophenolate mofetil and tacrolimus (Group 2) with terms of patients and graft survival. We also analyzed the spectrum of infections across the two groups. Study Design: A retrospective observational study was conducted from 1995 to 2014 at St. John's Medical College and Hospital, Bengaluru. Patients received treatment as per standard protocol. Setting and Participants: Renal transplant recipients who regularly visited outpatient department. Analytical Approach: Statistical analysis was done by using SPSS 19 software. Continuous variables were analyzed using Student's t-test. Pearson's correlation test used for correlating variables. Kaplan–Mere curve used for calculating survival. Primary Outcomes: Rejection rates were similar across both the groups. The patient survival was 65% and 70% in Group 1 and 2 at 5 years, respectively. Graft survival was 65% and 75% in Group 1 and 2 at 5 years. Secondary Outcome: Bacterial and fungal infections were more common in Group 1, whereas viral infections were more in Group 2. In addition, infections tend to occur early in Group 2. Limitations: Single center, retrospective study. Conclusion: Patient and graft survival were similar across both the groups.

Keywords: Azathioprine, infections, mycophenolate mofetil, rejections, survival


How to cite this article:
Sathish R, Marisiddappa L, Kedlaya P, Nagaraj V, Kruthika D M. Graft and survival outcome in renal transplant patients receiving cyclosporine and azathioprine versus tacrolimus and mycophenolate mofetil: A single-center retrospective observational study. Indian J Transplant 2021;15:50-5

How to cite this URL:
Sathish R, Marisiddappa L, Kedlaya P, Nagaraj V, Kruthika D M. Graft and survival outcome in renal transplant patients receiving cyclosporine and azathioprine versus tacrolimus and mycophenolate mofetil: A single-center retrospective observational study. Indian J Transplant [serial online] 2021 [cited 2021 Jul 30];15:50-5. Available from: https://www.ijtonline.in/text.asp?2021/15/1/50/312751




  Introduction Top


Since early days of renal transplant, steroid, and azathioprine (AZA) were backbone of immunosuppression armamentarium. AZA is an imidazole derivative of 6-mercaptopurine and inhibits nucleic acid synthesis, suppressing cell-mediated hypersensitivity, and altering antibody production. In 1990s, cyclosporine (CYs) was introduced which dramatically improved graft survival. Since then, CYs has been regularly used in renal transplant. In early nineties, mycophenolate mofetil (MMF) was introduced and slowly AZA was changed to MMF. MMF is a recently developed immunosuppressive drug, which acts to inhibit T and B cell proliferation by blocking the production of guanosine nucleotides required for DNA synthesis. Each drug has its own safety profile and effect on long-term graft and patient survival. A randomize 3 arm parallel group open labelled prospective study performed in 15 north American centers compared 3 regimens TAC+AZA , CYS+MMF and TAC+MMF. The steroid dose was same in each arm. TAC+MMF regimen had less Acute rejection at 1 year.[1] In Cochrane data base issue 12 2015 meta analysis of randomized controlled trial showed that risk of graft loss including death and risk of biopsy proven acute rejection including antibody mediated rejection was less in MMF group compared to AZA group.[2]

Three major, prospective, randomized clinical trials who received an immunosuppressive regimen that included CYs and steroids found a significantly lower proportion of patients with a first rejection episode on MMF 2 g/day (33.2%) or 3 g/day (35.0%) than on AZA or placebo (50.3%).[3],[4],[5],[6] Based on these trails, MMF progressively replaced AZA as a part of standard treatment for preventing rejection in most centers worldwide.

However, the Mycophenolate Steroids Sparing (MYSS) study found that in renal transplant recipients (RTRs) who were on immunosuppressive therapy with the CYs, MMF was not better than AZA in preventing acute rejection at 21 months after transplantation.[7] Furthermore, the MYSS follow-up randomized, controlled clinical trial showed that the long-term risk/benefit profile of MMF and AZA therapy in kidney transplantation are similar. Because the costs for standard treatment with MMF remarkably exceed those of AZA, standard immunosuppression regimens for kidney transplantation should perhaps include AZA rather than MMF.[7]

However, there is a paucity of data from the Indian scenario regarding the same.

Aim of study

  1. Primary aim of our study was to assess the patient survival and graft survival across the IS regimens groups (1 and 2)
  2. Secondary aim was to analyze the spectrum of infection between two groups.



  Materials and Methods Top


This was a single-center retrospective observational study. Patients' data were collected from 1995 to 2014. Medical records of all patients were scrutinized in systematic manner after obtaining ethical committee clearance.

A total of 359 kidney transplantations were performed in St. John's Medical College and Hospital, Bengaluru, between 1995 and 2016. Two hundred and forty-nine consecutive kidney transplant patients whose records were complete were included in the study. Of these, 158 patients were on CYs, AZA, and steroid combination (Group 1). Ninety-one patients were on tacrolimus (TAC), MMF and steroid combination (Group 2) [Figure 1]. Majority of transplants were live related with haplo match and all were complement-dependent cytotoxicity cross-match negative pretransplant.
Figure 1: The study design

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Inclusion criteria were: (1) patient on regular follow-up and compliant with immunosuppression medications (IS) and (2) IS was maintained the same throughout the study except during acute rejection.

Exclusion criteria: (1) patients whose immunosuppression was modified from AZA to MMF and vice versa (2) those who were not on regular follow-up.

Our center immunosuppressive protocol were as follows: Induction used was antithymoglobulin (1 mg/kilo body weight for 3 days) or basiliximab 20 mg before surgery followed on day 4 postoperative for all deceased donor recipients and sensitized recipients.

The maintenance immunosuppressive protocol consisted of TAC, MMF or AZA, CYs, and steroids. All patients received perioperative methylprednisolone 1 g intravenous (iv) once a day for 3 days followed by oral Prednisolone (1 mg/kilo body weight) once a day from the next day, tapered to 20 mg on day 30. After that, it was gradually tapered to 10 mg at the end of 3 months. Most of the patients were receiving prednisolone 10 mg once a day after 6 months, if their course was uneventful. TAC was started on day minus 3 of transplant at a dose of 0.1 mg/kg/weight in two divided doses and TAC whole blood trough levels were done on day 4 and 8 during hospitalization, and after that at least once a month or whenever required. TAC levels were maintained between 8 and 12 ng/ml in first 3 months, 6–8 ng/ml next 3 months and 4–6 ng/ml thereafter. MMF was started day minus 3 of transplant in a dose of 30 mg/kg body weight twice a day or AZA in a dose of 2 mg/kg/weight once a day. CYs dose 8 mg/kg BW/day. Initial C0 trough level maintained at 200–400 ng and later after 6 months between 100 and 200 ng. The dose of MMF was adjusted based on total white blood cell (WBC) and any intolerance to MMF. The dose of AZA was adjusted based on total WBC and serum transaminase levels.

These patients were followed up twice weekly in the 1st month, once a week for the next 2 months, once in 2 weeks for the next 3 months, once a month thereafter and once in 3–6 months after 1 year. At each visit, complete blood counts, blood urea nitrogen, serum creatinine, and other investigations were done as per protocol at our center. Graft biopsy was done in the event of graft dysfunction except when a patient did not give consent or was unsuitable for a biopsy. In the event of biopsy-proven or clinical rejection, the patients were treated initially with iv methylprednisolone 500 mg-1 g infusion for 3–5 days. If the response was not satisfactory, then he/she was labeled as steroid resistant and was treated with thymoglobulin at a dose of 1 mg/kg/dose at 3 doses. Anti-thymocyte globulin (ATG) was always given after a kidney biopsy. A patient was labeled as having refractory rejection, if he did not respond to pulse steroids and ATG. Graft survival was defined as time taken from transplantation to failure (back on dialysis after transplant). The requisite criteria for infection were the presence of fever and features of the systemic inflammatory response syndrome with a suspected source of infection. Asymptomatic patients with microbiological evidence of infection either by culture or using serology were also included in the study.

Statistical analysis

Statistical analysis was done using SPSS version 19 (IBM Corp. Released 2019. IBM SPSS Statistics for Windows, Version 26.0. Armonk, NY: IBM Corp.). Student t-test was done for categorical variable and Chi-square test for noncategorical variable. Kaplan–Meier survival curves were used to analyze the survival. Descriptive and inferential statistical analysis has been carried out in the present study. Results on continuous measurements are presented on mean ± standard deviation and results on categorical measurements are presented in number (%).

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, initials would not be published, and all standard protocols will be followed to conceal their identity.

Ethics statement

Ethical clearance was obtained from St Johns Medical College and Hospital, Bengluru. IEC no 1/694/2020. All protocols were followed as per Declaration of Helsinki.


  Results Top


The basic demographic data are depicted as in [Table 1]. Chronic glomerulonephritis was most common cause of chronic kidney disease (CKD). Majority were live related donors. Group 1 comprised of 158 patients and Group 2 with 91 patients [Table 1]. Four (2.5%) patients in Group 1 and 2 (2.2%) in Group 2 had acute cellular rejection [Table 2]. Three patients in each group had steroid-resistant acute rejection. Two patients in each group had graft loss due to rejection. The most common cause for delayed graft functions was acute cellular rejection (4 in both the groups) followed by acute tubular necrosis (3 in each group). 51 (32.3%) patients in Group 1 and 5 (5.5%) patients in Group 2 had interstitial fibrosis and tubular atrophy (IFTA) and one patient in each group had late acute antibody mediated rejection.
Table 1: Demographics of the patients

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Table 2: Acute and chronic rejection

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Hepatitis C was more in Group 1 compared to Group 2 (19 [12.58%] vs. 7 [6.48%]). Urinary tract infections (UTIs) was the most common infections across both the groups 31 (20.5%) versus 14 (12.96%) followed by bacterial pneumonia (13 [8.60%] vs. 11 [10.1%]). Cytomegalovirus (CMV) infection was seen in 13 patients in each group. Approximately 6% of patients developed tuberculosis (TB) in each group. The mean duration of occurrence of infection was 60 months in Group 1 compared to 33.5 months in Group 2. Fungal infections were more common in Group 1 compared to Group 2 (34 [21.5%] vs. 8 [8.8%]). The incidence of CMV infection was low overall, 13/158 (8.6%) in the Group 1 and 13/91 (12.03%) in the Group 2. Two patients in the Group 2 had BK virus infection [Table 3].
Table 3: Overall infection episodes in the two groups

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The last follow-up mean serum creatinine was 1.62 ± 1.31 mg/dl in the Group 1 and 1.74 ± 1.43 mg/dl in the Group 2. Five (3.2%) patients in the Group 1 and 1 (1.1%) patient in the Group 2 lost their grafts [Table 4]. The causes of graft loss in the both the groups were chronic allograft injury. A total of 85 patients died during the follow-up, 70 (44.3%) in the Group 1 and 15 (16.5%) in the Group 2 [Figure 2]. The most common cause of death in both the groups was infections followed by cardiovascular events. 62 (39.2%) patients in Group 1 and 62 (68.1%) patients in Group 2 had stable graft functions [Figure 3].
Table 4: Patient and graft outcome

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Figure 2: Kaplan–Meier survival curve showing graft survival

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Figure 3: Kaplan–Meier survival curve showing patient survival

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  Discussion Top


Optimal immune suppression is key to success of renal transplant. Immunosuppression needs to be adjusted individually based on patients' clinical and financial status. Since in our country, majority of CKD stage five patients are from poor socioeconomic status it becomes mandatory to consider immunosuppression with less cost, so they adhere to therapy and more compliant.[8] At the same time, we need to see whether outcome with low cost immunosuppression is in par with recent expensive immunosuppressive regimen. Hence, this study was undertaken to evaluate the graft and patient outcome across the two groups of immunosuppression. AZA was used until 2006 as standard antiproliferative agent in our center but later on we switched to MMF. AZA is still occasionally used when patients could not afford MMF.

In our study, we found that both the groups were in par when we compared rejection and overall outcome. Our results were comparable to study done by Bansal et al. from AIMS New Delhi.[9] In 2002, Webster et al. compared the efficacy of TAC with CYs in reducing the risk of graft rejection and improving graft survival. This study showed that using TAC instead of CYs in 100 patients prevented 12 rejection episodes and 2 graft loss. This comes at the cost of having five patients with diabetes mellitus after transplantation. However, there was no increase in the incidence of infection or malignancy.[10] In our study, IFTA was more common in Group 1, probably because the patients in group were transplanted earlier and followed up for a longer period of time.

The mean calculated glomerular filtration rate was higher and the incidence of biopsy proven rejection rate was lower in the group with low-dose TAC immunosuppression as shown in the symphony trial.[11] In our study, last follow-up mean creatinine was 1.62 ± 1.31 in Group 1 while it was 1.74 ± 1.43 in Group 2, which was almost similar across both the groups. The analysis of data from the United States Renal Data System suggests that patient survival for living donor transplants 98% after 1 year and 93% at 5 years,[12] whereas in our study, the patient survival was 65% and 70% in Group 1 and 2 at 5 years, respectively. Similarly, graft survival was 65% and 75% in Group 1 and Group 2 at 5 years.

Group 1 had higher incidence of infection compared to Group 2 and mean duration of occurrence of infections was 60 months compared to 33 months in Group 2. This implies infections occurred early in Group 2. In addition, bacterial and fungal infections were more common in Group 1, whereas viral infections were more common in Group 2 in our study. A retrospective cohort study of 28,942 primary renal transplant recipients from the U. S. Renal Data System database revealed a cumulative UTI incidence of 17% during the first 6 months after transplantation; at 3 years, the incidence was 60% for women and 47% for men, this in comparison to 21% in Group 1 and 13% in Group 2.

About 70% of all RTRs experience at least one infection episode by 3 years. Infections are responsible for 18% of all deaths with functioning grafts in the US, and are the leading cause of death in the developing countries.[13] Our results show that infectious disorders are a significant cause of morbidity and mortality across both the groups. There were 110 infectious episodes in Group 1 and 40 infection episodes in Group 2. Postsurgical bacterial infections usually occur in the 1st month after transplantation; opportunistic infections (particularly CMV) are significant at 1–6 months' posttransplantation and a mixture of community acquired and opportunistic infections are usually identified in late posttransplant period in previous studies. In our study, the infections were seen commonly after 1 year of transplantation. The immunosuppression-related TB and fungal infections predominate during this late period, accounting for the grater graft dysfunction, sepsis, and death. The reported prevalence of posttransplant TB varies between 2% and 15% in Asia and other countries.[13] In our study, the occurrence rate of posttransplant TB is 6%. The high prevalence of TB could be due to the fact that India is the world capital of TB with maximum risk of exposure.

Limitations of the study

There were few limitations in our study: single-center study, cost calculation of the immunosuppression was not performed, proteinuria and adverse effects of the drugs were not recorded. Furthermore, the groups were heterogeneous in few aspects, and induction regimen was not uniform across the groups. There was shorter follow-up for few patients, the use of prophylactic therapy and anti-hepatitis C virus drugs in later period was not recorded.


  Conclusion Top


We conclude that in our setting both groups showed almost comparable results hence AZA based regimen can safely be used in patients who cannot afford MMF. However, infections tend to occur early and viral infections were more common in MMF group.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Johnson C, Ahsan N, Gonwa T, Halloran P, Stegall M, Hardy M, et al. Randomized trial of tacrolimus (Prograf) in combination with azathioprine or mycophenolate mofetil versus cyclosporine (Neoral) with mycophenolate mofetil after cadaveric kidney transplantation. Transplantation 2000;69:834-41.  Back to cited text no. 1
    
2.
Wagner M, Earley AK, Webster AC, Schmid CH, Balk EM, Uhlig K. Mycophenolic acid versus azathioprine as primary immunosuppression for kidney transplant recipients. Cochrane Database Syst Rev 2015;(12):CD007746.  Back to cited text no. 2
    
3.
Remuzzi G, Cravedi P, Costantini M, Lesti M, Ganeva M, Gherardi G, et al. Mycophenolate mofetil versus azathioprine for prevention of chronic allograft dysfunction in renal transplantation: The MYSS follow-up randomized, controlled clinical trial. J Am Soc Nephrol 2007;18:1973-85.  Back to cited text no. 3
    
4.
Sollinger HW; for the US Renal Transplant Mycophenolate Mofetil Study Group: Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. Transplantation 1995;60:225-32.  Back to cited text no. 4
    
5.
A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation. The Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group. Transplantation 1996;61:1029-37.  Back to cited text no. 5
    
6.
European Mycophenolate Mofetil Cooperative Study Group: Placebo-controlled study of mycophenolate mofetil combined with cyclosporin and corticosteroids for prevention of acute rejection. Lancet 1995;345:1321-5.  Back to cited text no. 6
    
7.
Remuzzi G, Lesti M, Gotti E, Ganeva M, Dimitrov BD, Ene-Iordache B, et al. Mycophenolate mofetil versus azathioprine for prevention of acute rejection in renal transplantation (MYSS): A randomised trial. Lancet 2004;364:503-12.  Back to cited text no. 7
    
8.
Mani MK. Prevention of chronic renal failure at the community level. Kidney Int Suppl 2003;(83):S86-9. doi: 10.1046/j.1523-1755.63.s83.17.x.  Back to cited text no. 8
    
9.
Bansal SB, Saxena V, Pokhariyal S, Gupta P, Kher V, Ahlawat R, et al. Comparison of azathioprine with mycophenolate mofetil in a living donor kidney transplant programme. Indian J Nephrol 2011;21:258-63.  Back to cited text no. 9
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10.
Webster AC, Woodroffe RC, Taylor RS, Chapman JR, Craig JC. Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: Meta-analysis and meta-regression of randomised trial data. BMJ 2005;331:810.  Back to cited text no. 10
    
11.
Ekberg H, Tedesco-Silva H, Demirbas A, Vítko S, Nashan B, Gürkan A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med 2007;357:2562-75.  Back to cited text no. 11
    
12.
US Renal Data System: Annual Data Report; 2008. Available from: http://www.usrds.org/adr. [Last accessed on 2008 Dec 15].  Back to cited text no. 12
    
13.
Singh N, Paterson DL. Mycobacterium tuberculosis infection in solid-organ transplant recipients: Impact and implications for management. Clin Infect Dis 1998;27:1266-77.  Back to cited text no. 13
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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