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Table of Contents
REVIEW ARTICLE
Year : 2018  |  Volume : 12  |  Issue : 3  |  Page : 165-168

Comparison of patient and graft survival in tacrolimus versus cyclosporine-based immunosuppressive regimes in renal transplant recipients – Single-center experience from South India


Department of Nephrology, NU Hospitals, Bengaluru, Karnataka, India

Date of Web Publication28-Sep-2018

Correspondence Address:
Dr. Kiran Chandra Patro
Department of Nephrology, NU Hospitals, Bengaluru, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_6_18

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  Abstract 


Studies have shown better graft function and reduced acute rejection rates among renal transplant recipients who were on Tacrolimus (Tac)-based immunosuppression regimens as compared to cyclosporine (CsA)-based regimens in the first year. However, the long-term follow-up data did not reveal better outcomes in the Tac-based regimens. In view of the short term benefits, the trend has been to change to Tac-based regimens off late. Data from the Indian subcontinent are, however, sparse. We, therefore, looked at our data to ascertain if Tac-based regimen does have better outcomes in our population. We studied a total of 108 individuals who underwent renal transplantation between January 2007 and June 2013, with a mean follow-up of 38.22 months (comparable to both groups). In our group, males constituted 77.8%,; and among the 108 individuals, 16.7% were diabetics. New-onset diabetes after renal transplantation was more common in the Tac group (21 vs. 12 and was statistically significant [P = 0.03]). At the last follow-up, serum creatinine was higher in the CsA group (1.77 mg/dl vs. 1.35 mg/dl) and was statistically significant (P = 0.03). Individuals requiring hemodialysis were also significantly higher in the CsA group (9 vs. 2; P = 0.05). The patient survival was similar in both groups (1-year and 5-year follow-up); however, graft survival was better in Tac group as compared to CsA group (0.94 vs. 0.88 at 1 year and 0.85 vs. 0.72 at 5 years).

Keywords: Comparison, cyclosporine, renal transplant recipients, renal transplantation, tacrolimus


How to cite this article:
Patro KC, Ramakrishnan S, Kumar S, Roopa J, Dilip R. Comparison of patient and graft survival in tacrolimus versus cyclosporine-based immunosuppressive regimes in renal transplant recipients – Single-center experience from South India. Indian J Transplant 2018;12:165-8

How to cite this URL:
Patro KC, Ramakrishnan S, Kumar S, Roopa J, Dilip R. Comparison of patient and graft survival in tacrolimus versus cyclosporine-based immunosuppressive regimes in renal transplant recipients – Single-center experience from South India. Indian J Transplant [serial online] 2018 [cited 2018 Nov 21];12:165-8. Available from: http://www.ijtonline.in/text.asp?2018/12/3/165/242440




  Introduction Top


In renal transplantation, the immunosuppression plays a major role in maintaining the graft and has an impact on both the graft and the patient survival; however various other factors such as associated comorbidities, duration on dialysis, ethnicity, and timing of renal transplantation do play a significant role. With the advent of triple immunosuppression regimens, the graft survival has improved with a decrease in the episodes of graft rejection. Various studies have revealed a better graft survival in the tacrolimus (Tac)-based regimen as compared to cyclosporine (CsA)-based regimen. Moreover, there is a trend to change to Tac-based regimens in the Indian subcontinent.[1],[2],[3],[4] However, there is scarcity of similar Indian data to substantiate the same.[5] We looked at our own data to assess how these two regimen groups fared.

Aim

The aim of this study was to assess the efficacy and outcome of Tac- and CsA-based immunosuppression regimes in renal transplant recipients.


  Materials and Methods Top


Individuals with chronic kidney disease Stage 5 who underwent renal transplantation between January 2007 and June 2013 in our hospital (a tertiary care nephrology urology center) were randomized alternately to CsA- or Tac-based regimen and were included in the study.

Exclusions: Cadaver donor recipients (4) and recipients who had surgical complications requiring graft nephrectomy in the immediate posttransplant period (3) were excluded from the analysis.

Parents, children, siblings, and spouse were the donors for living donor transplantation. Alternate transplant recipients were randomized to Tac-based or CsA-based regimens. Mycophenolate mofetil (MMF) and azathioprine (AZA) were chosen on the basis of degree of matching on HLA typing, preexisting viral hepatitis, and affordability for MMF (as expressed by the patient before transplantation). Interleukin-2 receptor antagonist (IL-2) was added to the regime if there was no match on HLA typing.

Data were collected from the medical records for the analysis. An “intention to treat”, analysis was performed on the collected data for the following events: biopsy-proven acute rejection (BPAR); infections (patients who had tuberculosis, cytomegalovirus, and fungal infection in the posttransplant period were analyzed); new-onset diabetes mellitus after transplantation (those who required management with anti-diabetic medications for at least 3 months were included for the analysis), graft survival, and patient survival. Recipients who had not reported to follow-up either in person or by communication beyond 6 months were censored for analysis at their last visit date.

Categorical variables were analyzed using Fisher's exact test and unpaired t-test; patient survival, graft survival, and death-censored graft survival at 1 year and 5 years were calculated using Kaplan–Meier survival probability estimate.


  Results Top


  • Total number of transplants 108 (CsA group 56 and Tac group 52)
  • Males 84 (77.8%) (46 CsA and 38 Tac [P = 0.35])
  • Diabetes mellitus 18 (16.7%)
  • Follow-up (mean, in months) 38.22 (1–88); CsA group 37.23 and Tac group 39.22
  • Donors (average age 40.03 year) Spouses the most common followed by parents and siblings (no significant statistical difference in groups)
  • Age of recipients (mean age) 37.21 years (in CsA group) and 34.42 years (in Tac group) – younger population was noted in the Tac group but was not statistically significant (P = 0.17).


The use of MMF (18 in CsA group and 22 in Tac group) versus AZA (38 in CsA group and 30 in Tac group) did not statistically affect the rejection rate or the infection rate (P = 0.32). The use of MMF or AZA did not have any significant statistical impact on the graft or the patient survival in our study.

The intention of ours was to treat, and hence, where required, AZA was changed to MMF among 20 patients (13 in CsA group and 7 in Tac group) if there were transaminitis (3 cases), if Calcineurin-inhibitor dose was required to be lowered due to toxicity (two cases: one in CsA group and one in Tac group), acute tubular injury or renal dysfunction during follow-up (11 cases: 6 in CsA group and 5 in Tac group), or when biopsy proven rejection (four cases: three in CsA and one in Tac group) was noted. However, when the data were corrected for this switch too, there was no statistically significant difference noted.

The use of IL-2 receptor blocker (20 in CsA group vs. 15 in Tac group) was similar in both groups and was not statistically significant (P = 0.53).

As is already known the Tac group did have a significantly higher incidence of new-onset diabetes after transplantation (NODAT) (21 in Tac group vs. 12 in CsA group) which was statistically significant (P = 0.03); however, it did not have any adverse effect on the patient or the graft survival.

Infections (13 in CsA group; 6 in Tac group; P = 0.13), BPARs (16 in CsA group; 10 in Tac group; P = 0.27), [Table 1] and lipid abnormalities (12 in CsA group; 7 in Tac group; P 0.32) were comparable in both the groups and there was no statistical difference [Table 2].
Table 1: Comparative data in CsA group and Tac group

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Table 2: Comparitive data between CsA and Tac groups: renal functions, dialysis requirement and mortality

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Serum creatinine at 1-year follow-up (1.56 mg/dl in CsA group; 1.4 mg/dl in Tac group) was similar (P = 0.17); however, serum creatinine at 5-year follow-up (1.77 mg/dl in CsA group; 1.35 mg/dl in Tac group) was significantly higher in the CsA group (P = 0.03) suggesting a better graft function in the Tac group than in the CsA group at the end of 5 years. Similarly, individuals requiring renal replacement therapy (9 in CsA group and 2 in Tac group) were significantly higher in the CsA group (P = 0.05) than in the Tac group suggesting a better graft survival in the Tac group than the CsA group [Table 2].

Mortality, however, was similar in both the groups (7 in CsA group; 6 in Tac group; P = 1.0) [Table 2].

At the end of 1 year, statistical analysis by the Kaplan–Meier survival probability revealed the following:

  1. An average overall patient survival was 0.87; 0.92 (0.81–0.97) in the CsA group and 0.94 (0.83–0.98) in Tac group
  2. Average graft survival in both groups was 0.78; 0.88 (0.75–0.94) in the CsA group and 0.94 (0.83–0.98) in Tac group.


At the end of the 5th year:

  1. Average overall patient survival was 0.93; 0.86 (0.74–0.93) in the CsA group and 0.87 (0.74–0.94) in the Tac group
  2. Average graft survival in both the groups was 0.90; 0.72 (0.58–0.0.82) in the CsA group and 0.85 (0.72–0.93) in the Tac group.


Death-censored graft survival:

  1. At the end of 1 year was 0.88; 0.94 (0.84–0.98) in CsA group and 1.0 (0.91–1.0) in Tac group
  2. At the end of 5 years was 0.97; 0.81 (0.68–0.90) in CsA group and 0.95 (0.86–0.99) in Tac group.


The patient survival in both the groups was similar at both 1 year and 5 years; however, there was a significant difference in the graft survival at the end of 5 years - with Tac group showing a better graft survival as compared to CsA group at the end of 5 years. Death-censored graft survival was also better in the Tac group as compared to the CsA group [Table 3], [Table 4], [Table 5].
Table 3: Patient survival in CsA and Tac groups

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Table 4: Graft survival in CsA and Tac groups

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Table 5: Death censored graft survival in CsA and Tac groups

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The limitations of this study include the lack of adequate power and lack of long-term data. The drug levels of Tac or CsA were not checked at regular intervals; as in our center, (the drug levels are checked in the 1st-year post transplantation and thereafter only as and when clinically or biochemically indicated). We, therefore, were not able to comment if drug-level monitoring on regular basis would have made any statistical difference to the outcome.


  Discussion Top


With triple immunosuppression-based regimens, both graft and patient survival have improved. With the advent of Tac-based regimens, various studies have indicated reduction in acute rejection episodes and better renal function at the end of 1 year as compared to CsA-based regimen. The incidence of postrenal transplantation diabetes mellitus (PTDM) was higher in the Tac-based immunosuppression as is anticipated and so were neurological and gastroenterological side effects more common in Tac-based regimens as compared to CsA-based regimens. Blood pressure records and dyslipidemia were lower in the Tac-based immunosuppression as compared to the CsA-based immunosuppression. Cardiovascular morbidity and mortality were higher in the CsA-based immunosuppression in the immediate postrenal transplantation period. However, long-term studies have shown no great benefit with Tac-based regimens as compared to the CsA-based regimens.[1],[2],[4],[6],[7]

Our study did reveal a higher incidence of PTDM in the Tac-based immunosuppression as compared to CsA-based immunosuppression, but there was no significant change in the dyslipidemia, cardiovascular deaths, or blood pressure measurements. There was also no significant difference in the number of BPAR in both the groups, but the serum creatinine values were significantly lower in the Tac-based regimen as compared to CsA-based regimen. Further, the requirement for dialysis was also higher in the CsA-based regimen as compared to the Tac-based regimen. The number of infections was higher in the CsA group, though it was not statistically significant. The overall graft survival was better in Tac-based regimen both at 1-year and 5-year follow-up as compared to the CsA-based regimen. This holds true to both average graft survival and death-censored graft survival. The patient survival though has been almost similar in both the groups both at the end of 1 year and at the end of 5 years.

Hence, unlike previous studies, our study did not show any significant reduction in the acute rejection rates with Tac-based regimens across all the donors (both HLA matched and mismatched), but there was significantly better renal function among the Tac-based regimen both at 1 year and at 5 years as compared to CsA-based regimens.

However, longer follow-up will be required to look at malignancy rates (as our malignancy rates have been low so far) and long-term graft and patient survival in both the groups.

With the present trend of better graft survival and better graft function in Tac-based regimens, we felt that it was better to rely on Tac-based regimen in our population. Furthermore, with lower costs of Tac in India (cheaper than that of CsA), Tac-based regimens seem to be the way forward as of now.


  Conclusions Top


Graft survival and graft function was better in the Tac group at 1 year and 5 years as compared to the CsA group, though the patient survival was the same. There was, however, no significant difference in the number of rejection episodes in both the groups. CsA group had more episodes of infection as compared to the Tac group; however, it was not statistically significant. There was statistically significant increase in the incidence of new-onset diabetes after transplantation in the Tac group as compared to the CsA group (as is expected).

Following this study analysis, we have changed the practice at our center and shifted over to Tac-based regimen!

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Webster A, Woodroffe RC, Taylor RS, Chapman JR, Craig JC. Tacrolimus versus cyclosporin as primary immunosuppression for kidney transplant recipients. Cochrane Database Syst Rev 2005;4:CD003961.  Back to cited text no. 1
    
2.
Jurewicz WA. Tacrolimus versus cyclosporin immunosuppression: Long-term outcome in renal transplantation. Nephrol Dial Transplant 2003;18 Suppl 1:i7-11.  Back to cited text no. 2
    
3.
Patel DD, Modi KP, Patel AK. Prescription trends of immunosuppressant drugs in Indian renal transplant patients. Int J Pharm Sci Drug Res 2015;7:334-9.  Back to cited text no. 3
    
4.
Goldfarb-Rumyantzev AS, Smith L, Shihab FS, Baird BC, Habib AN, Lin SJ, et al. Role of maintenance immunosuppressive regimen in kidney transplant outcome. Clin J Am Soc Nephrol 2006;1:563-74.  Back to cited text no. 4
    
5.
Varma PP, Hooda AK, Sinha T, Chopra GS, Karan SC, Sethi GS, et al. Renal transplantation - An experience of 500 patients. Med J Armed Forces India 2007;63:107-11.  Back to cited text no. 5
    
6.
Martins L, Ventura A, Branco A, Carvalho MJ, Henriques AC, Dias L, et al. Cyclosporine versus tacrolimus in kidney transplantation: Are there differences in nephrotoxicity? Transplant Proc 2004;36:877-9.  Back to cited text no. 6
    
7.
Knoll GA, Bell RC. Tacrolimus versus cyclosporin for immunosuppression in renal transplantation: Meta-analysis of randomised trials. BMJ 1999;318:1104-7.  Back to cited text no. 7
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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