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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 17  |  Issue : 1  |  Page : 1-7

Short-term results of calcineurin-free and steroid-free immunosuppression protocol in live-donor renal allotransplantation: a prospective, randomized, controlled study


1 Nephrology Unit, Urology and Nephrology Center, Mansoura University, Mansoura, Egypt
2 Department of Internal Medicine, Zagazig University, Zagazig, Egypt
3 Pathology Unit, Urology and Nephrology Center, Mansoura University, Mansoura, Egypt
4 Urology Department, Urology and Nephrology Center, Mansoura University, Mansoura, Egypt

Date of Submission08-Jan-2017
Date of Acceptance30-Jan-2017
Date of Web Publication13-Jun-2017

Correspondence Address:
Ahmed I Kamal
Nephrology Unit, Urology and Nephrology Center, Mansoura University, Mansoura, 35516
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jesnt.jesnt_3_17

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  Abstract 

Objectives
The aim of this study was to investigate the efficacy and safety of steroid-free and calcineurin-free immunosuppressive regimen using sirolimus (SRL) and mycophenolate mofetil (MMF) after 3 months of kidney transplantation in low-risk, living, renal allotransplant recipients.
Patients and methods
We carried out a randomized, prospective, and controlled study including 50 low immunological risk patients who received their living renal allograft in the period between July 2012 and June 2014 at Mansoura urology and nephrology center’s dialysis and renal transplantation unit. All the recruited patients were regularly followed-up for 12 months after transplantation at our center.
Results
Patients were randomized 3 months after transplantation either to continue on tacrolimus and MMF or to be shifted to SRL with MMF. At 6 months after transplantation, the value of the mean estimated glomerular filtration rate was significant higher in the SRL group versus the tacrolimus group (144.7±28.5 vs. 128.4±44.9, respectively, P=0.039). However, at the end of the year, this significant difference disappeared between both groups. Twenty-four hours protein and hypercholesterolemia were significantly higher in the SRL group. On the other hand, hypertension at 1 year after transplantation was significantly lower in the SRL group. We experienced only one grade 1A acute cellular rejection in the SRL group and only borderline changes in each group with stable graft functions.
Conclusion
Steroid-free, calcineurin-free immunosuppressive protocol is a suitable choice for low immunological risk renal transplant recipients but with a close and strict follow-up plan to avoid and treat any unwanted events. Adopting steroid-free, calcineurin-free regimens should be accompanied with protocol biopsy assessment to discover any histopathological abnormalities even before they are clinically detectable.

Keywords: calcineurin inhibitors free, minimization, renal transplantation, steroid free


How to cite this article:
Kamal AI, El Wasif SM, Mostafa E, Abdelrahim MM, Elsherbiny EM, Shokeir AA, Bakr MA. Short-term results of calcineurin-free and steroid-free immunosuppression protocol in live-donor renal allotransplantation: a prospective, randomized, controlled study. J Egypt Soc Nephrol Transplant 2017;17:1-7

How to cite this URL:
Kamal AI, El Wasif SM, Mostafa E, Abdelrahim MM, Elsherbiny EM, Shokeir AA, Bakr MA. Short-term results of calcineurin-free and steroid-free immunosuppression protocol in live-donor renal allotransplantation: a prospective, randomized, controlled study. J Egypt Soc Nephrol Transplant [serial online] 2017 [cited 2017 Aug 16];17:1-7. Available from: http://www.jesnt.eg.net/text.asp?2017/17/1/1/207902


  Introduction Top


End-stage renal disease is one of the greatest healthcare burdens. As of now, the treatment of choice for end-stage renal disease is kidney transplantation. The role of immunosuppression is pivotal in kidney transplantation [1]. To dampen the allograft immune response, adequate levels of immunosuppression should be maintained. However, slow decrease in chronic immunosuppressive levels is targeted to help lower the overall risk of malignancy and infections, which are closely associated with the degree of immunosuppression [2]. Unfortunately, the long-term outcome has not significantly changed over the decades despite decreased rates of acute rejection episodes [3]. Different immunosuppression protocols have been used aiming to decrease the incidence of chronic allograft rejection, the main cause of long-term allograft loss [4]. With long-term use of glucocorticoids in the field of transplantation, many side-effects have started to become obvious. These side-effects include, and are not limited to, worsening of pretransplant diabetes, increased incidence of post-transplant diabetes mellitus (PTDM), bone complications, delayed wound healing, dyslipidemia, worsening hypertension, and increased risk of cataract development [5]. Moreover, calcineurin inhibitors (CNIs)-induced nephrotoxicity is one of the well-recognized causes of chronic allograft toxicity, which contributes significantly to the unimproved long-term graft outcome [6]. Considering all these adverse effects, attention has been drawn long time ago toward steroid tapering aiming at steroid-free immunosuppressive regimens. This was associated with a significant decreased incidence of post-transplantation diabetes, hypertension, and bone complications [7]. Besides, diverse mechanisms to reduce or totally avoid the use of CNIs have been tried over the last decade [8],[9],[10]. The ideal immunosuppressive regimen that fits all kidney transplant patients is still a frozen dream. The main immunosuppressive agents being currently used for maintenance therapy are corticosteroids, azathioprine, cyclosporine, tacrolimus (TAC), mycophenolate mofetil (MMF), mycophenolate sodium, sirolimus (SRL), and everolimus [11]. Newer regimens have been studied over the last two decades concentrating on tailoring immunosuppressive protocols according to each patient’s immunological risk and tolerability to immunosuppressive agents and their expected side-effects. In our study, we aimed to explore the efficacy and safety of a protocol based on SRL and MMF, which is free of steroids and CNIs, trying to avoid a host of well-known side-effects linked to both these immunosuppressants.


  Patients and methods Top


The present study was a prospective, randomized, and open-labeled study that was performed to evaluate the efficacy and safety of steroid-free immunosuppressive regimens in 50 transplant recipients who received renal allografts from living, related kidney donors during the period between July 2012 and June 2014. Patients were selected from the renal transplantation unit at the Mansoura Urology and Nephrology Center. Patients were regularly followed-up for 1 year after transplantation. During the recruitment period, 166 chronic, renal failure cases received renal allografts from living donors at the Mansoura Urology and Nephrology Center. Of those patients, 107 patients fulfilled inclusion criteria for participating in the present study. Among them, there were 23 cases that needed steroids in the first 3 months because of different causes; 21 cases refused to be included in our study, and 13 cases had borderline changes in the 3-month protocol biopsy. Patient flow is summarized in [Figure 2]. On discharge, we prescribed methylprednisolone 500 mg/day for 5 days, which was stopped abruptly. The remaining 50 cases who participated in our study were followed-up for a year.

Inclusion criteria

Egyptian patients who received a renal allograft for the first time were recruited during the period between July 2012 and June 2014. They were classified as having low immunological risk and fulfilled the following criteria:

  1. HLA (Human Leukocytic Antigen) mismatches less than or equal to 50%.
  2. Panel reactive antibody lesser than 10% percent.
  3. Absence of a donor-specific antibody.
  4. Blood group compatibility.
  5. Immediate onset of graft function.


All 107 patients were maintained on steroid-free therapy (TAC and MMF) for the first 3 months, and then protocol biopsies were obtained. Thirteen patients had borderline changes with increased serum creatinine, and therefore they received pulse steroid 500-mg methylprednisolone/day for 5 days and then were maintained on steroid-free therapy. The decision to add maintenance oral steroids was put on hold until the second rejection episode to ensure the benefits of a steroid-free regimen as per our center’s protocol. Fifty patients with normal histopathology and BLC (Borderline changes) along with stable graft functions in protocol biopsies participated in our study. They were randomized into two groups.

Exclusion criteria

  1. Non-Egyptian patients who planned their regular follow-up in their places of residence.
  2. Retransplant recipients as they were considered as patients with high immunological risk.
  3. Patients with nephrotic syndrome as the original kidney disease leading to the development of end-stage kidney disease for fear of SRL-induced acceleration of allograft hyperfiltration injury.
  4. High immunological risk recipients who did not meet previously mentioned criteria.


Study design

This study was a prospective, randomized, and controlled trial. Patients were asked to visit the center if their 3-month protocol biopsy was normal, and all details of the study were discussed with them. Patients who agreed to participate in the study were randomized into two groups as shown in [Figure 1]. All patients recruited after having free protocol biopsies were randomized to either continue on the same regimen or were shifted from TAC to SRL.
Figure 1 Study design. MMF, mycophenolate mofetil

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Figure 2 Patient flow. MMF, mycophenolate mofetil; SRL, sirolimus

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Randomization was carried out by using sealed, opaque envelops after obtaining the patient’s consent for participating in the study. The main investigator was responsible for allocating patients into randomized treatment groups in a ratio of 1 : 1. The investigator and patients were not blinded for this open-label study.

Statistical analysis

Graft function difference was used as the primary efficacy marker to demonstrate that steroid-free and CNI-free protocol is not inferior to steroid-free and CNI-based regimen using chemical clearance for all patients and was supported by serum creatinine levels. Graft outcome was assessed at 3, 6 months, and 1 year. All available safety and efficacy criteria are presented by descriptive analysis and were compared between both groups using appropriate tests for unpaired and paired observations. All data were tabulated, and a statistical analysis was conducted at the end of the study. The statistical analysis was performed using commercial software programs (SPSS for Windows, version 20; SPSS Inc., Chicago, Illinois, USA).

Demographics, clinical history, and outcome data are summarized with means, SDs, and ranges. Differences in age, parity, and BMI between groups were compared by using two-tailed Student’s t-test for unpaired data. The χ2-test was used for categorical variables. A probability value of 0.05 was considered significant for all analyses.

The present study was designed and carried out after obtaining approval from the Mansoura University Institution Review Board for good clinical practice and with applicable local regulations with the ethical principles laid down in the Declaration of Helsinki.


  Results Top


A total of 166 patients were screened between July 2012 and June 2014, of whom 107 fulfilled inclusion and exclusion criteria. After obtaining biopsy results, 57 of them were excluded for different reasons as shown in [Figure 2]. The final sample included 50 patients. Baseline demographic characteristics are shown in [Table 1]. Both groups were comparable with regard to age, sex, blood groups, consanguinity of the donor, and even ischemia time. Different causes of original kidney disease were comparable between both groups. unfortunately, unknown cause original kidney disease was reported in about half of patients in both groups. Moreover, basal biochemical and hematological parameters were comparable between both groups at 3 months post-transplantation and before randomization ([Table 2]).
Table 1 Demographic data of recipients in both groups before renal transplantation

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Table 2 Comparison between both groups 3 months after transplantation and before randomization

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Primary and secondary outcomes

Renal functions

At 6 months after transplantation, the value of the mean estimated glomerular filtration rate was significant higher in the SRL group compared with the TAC group (144.7±28.5 vs. 128.4±44.9, respectively, P=0.039). However, at the end of the year, this significant difference disappeared between both groups as shown in [Table 4].

There was no significant difference at 6 months after transplantation between the SRL group and the TAC group regarding serum creatinine values (0.94±0.29 vs. 1.01±0.3 mg/dl respectively, P=0.59) ([Table 3]). In addition, after 1 year, there was no significant difference in serum creatinine levels between both groups (1.04±0.33 vs. 1.15±0.4 mg/dl in SRL and TAC groups, respectively, P=0.59) ([Table 4]).
Table 3 Comparison between both groups 6 months after transplantation

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Table 4 Comparison between both groups 1 year after transplantation

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Proteinuria, hypertension, and diabetes

Twenty-four hours urinary protein was significantly higher at both time points (6 and 12 months) in the SRL group compared with the TAC group ([Table 3] and [Table 4]). Only one patient reached nephrotic range proteinuria at the time between 3 and 6 months in the SRL group and was shifted to TAC. Proteinuria completely resolved after conversion.

Hypertension was significantly more prevalent in the TAC group ([Table 5]) affecting more than half of the patients at 1 year after transplant. [Table 5] highlights the incidence of some post-transplant complications in both groups assessed at 1 year after transplantation. At 6 months after transplantation, only one case in the TAC group developed PTDM.
Table 5 The prevalence of post-transplant complications of immunosuppression in both groups

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Histopathology

We encountered one case of acute cellular rejection in the SRL group who needed steroids after 6 months. Borderline changes were observed in each group, and none of them needed chronic steroid therapy. Another case in the SRL group showed significant proteinuria and was shifted from SRL therapy after the biopsy, which showed de-novo FSGS (Focal Segmental Glomerulosclerosis). The 1-year protocol biopsy showed a typical picture of membranous nephropathy in one patient in the TAC group without proteinuria. The patient received no treatment. The rest of the protocol biopsies at 1 year were normal.


  Discussion Top


Our study included 50 low-risk patients maintained on a steroid-free regimen (TAC and MMF) for 3 months and showed normal protocol biopsies after 3 months. Patients were randomized into two groups. Group 1 included 25 patients who continued on TAC and MMF. Group 2 included 25 patients who shifted from TAC to SRL and were maintained on SRL and MMF.

The mean age of group I was 30.90±9.072, whereas the mean age of group II was 27.50±10.87. There was no statistical difference in the age profile of both groups. This mean age was found to be in correlation with other studies [12],[13].

In our study, 23 cases out of 117 (20%) cases encountered different grades of early post-transplant rejection and needed steroid addition to their immunosuppression regimen during the first 3 months. This percentage is slightly higher than the 10% reported by Woodle et al. [14]. This finding can be explained by the use of different induction therapy, because in our study we used basiliximab, whereas Woodle et al. [14] used thymoglobulin. Use of basiliximab in our study as an induction therapy was clearly justified as all our participants were of low immunological risk profile, and there was no need for using stronger induction therapy as recommended by KDIGO guidelines [15].

Of 63 low-risk cases, maintained on steroid-free regimen and accepted to have a normal 3-month protocol biopsy, 13 cases had borderline changes according to the Banff classification, 2010.

These 13 (20%) cases had borderline changes in protocol biopsies; this percentage is significantly higher than that found in Nematalla et al.’s [12] study where it was only 12%. This may be due to the target trough level of TAC (5–10 ng/dl) being lower than that in the previously mentioned study (15–20 ng/dl) [12]. At that time, our practice was to target higher levels of CNIs, which changed later to guard against rapid development of chronic allograft dysfunction associated with using CNIs, especially with targeted high levels.

In our study, the rate of biopsy-proven acute cellular rejection was 8% in the SRL group (two cases, one of them was a subclinical rejection, out of 25 recipients); this finding differs from that found in a meta-analysis carried out by Yan et al. [16], and this may be due to our selection of low-risk individuals and our strict selection criteria besides the clearance of any subclinical changes in the graft by obtaining prerandomization 3-month protocol biopsies.

There was no statistically significant difference at 1 year with regard to serum creatinine, creatinine clearance, hemoglobin levels, white cell count, and platelet count in both groups. This agrees with the findings of Moore et al. [17]. However, a trend toward higher creatinine clearance was reached in the SRL group. On the other hand, we found significantly higher levels of serum cholesterol in the SRL group compared with the Tac group.

In our study, serum creatinine in the SRL group was lowered by 0.07 mg/dl at 1 year. The mean difference in creatinine clearance was 11 and 9 ml/min in 1 year. This is similar to the findings of a meta-analysis carried out by Yan et al. [16], where the differences were 6.21 and 13.96 ml/min at 1 and 2 years, respectively.

We found significantly higher incidence of dyslipidemia in both groups after 6 months and 1 year despite using statin. This agrees with the findings highlighted by Zeier et al. [18]. This shows the dyslipidemic effect of SRL independent of steroids after kidney transplantation.

Post-transplant hypertension was observed in 4% of patients in Nematalla et al.’s [12] steroid-free group. However, in our study, it was 35% in the TAC group, despite targeting lower Tac levels, and this may be because we recruited higher percentages of hypertensive patients in our study than the mentioned study.

PTDM was detected in 4% of patients in the steroid-free group in Nematalla et al.’s [12] study; this finding is similar to what we recorded (only one case) (5%).

Our study had a similar design to the multicenter Spare-the-Nephron trial but without the use of steroids. They included 299 low-risk patients assigned to either continue a center-specific CNI or be started on SRL between 30 and 180 days after transplantation. In this study, all patients continued to receive MMF (1–1.5 g twice daily) and corticosteroids dosed according to center. SRL was adjusted to trough levels of 5–10 ng/ml. By intention-to-treat analysis, the SRL group had a greater improvement in glomerular filtration rate (GFR) than the calcineurin group at 12 months. At 24 months, there was a trend toward greater improvement in GFR in the SRL group that was not statistically significant. There was no difference in the rate of acute rejection reported at 12 months; there was a nonsignificant trend toward a lower rate of rejection after 12 months in the SRL group. The rate of adverse events was the same between groups [19].

Rivelli et al. [20], found that there was no difference in serum creatinine in both groups (TAC and SRL based) at 3 months, whereas at 12 months, renal function was improved in the SRL group compared with the TAC group as measured by serum creatinine and creatinine clearance using MDRD (modification of diet in renal disease) equation.

These findings are similar to ours in spite of the fact that we used a steroid-free regimen, whereas they used steroids in their study.

The FREEDOM trial revealed a 12-month incidence of AR (Acute rejection) of 29.6% with steroid withdrawal. These findings disagree with our study, which found only 10% (2/20) of incidence in group 2 that continued on SRL and MMF, whereas in the TAC group no acute rejection was observed. This is might be because we selected low immunological risk patients [21].

Heilman et al. [22] reported that conversion from TAC and MMF to SRL and MMF at 1 month after transplantation in kidney recipients on rapid steroid withdrawal was poorly tolerated and did not improve GFR at 1 year. In this study, 63% of the patients in the SRL group withdrew during the 2-year period of the study compared with 18% in the TAC group, primarily related to rejection or medication adverse effects.

However, in our study, we found only 10% rejection in the TAC group and 20% in the SRL group. This may be because we selected low immunological risk patients and postponed shifting from TAC to SRL until the end of the 3rd month after renal transplantation, and randomization occurred only after normal histopathological findings in protocol biopsy.

The strength of our study is its prospective, randomized, and controlled design ensuring the benefit of covering the early post-transplant period with higher levels of immunosuppression and then tailoring the protocol according to the graft status. Another strength is having the protocol biopsy before randomization and at the end of the study, giving a chance to detect any mild change even at the histopathology level.

The weak points of our study include the limited number of patients. Moreover, having only recruited living donors may limit the applicability of results on widely used deceased organs.

These results will pave way for the concept of tailoring immunosuppressive protocols according to the immunological risk profile attempting to reach the minimum side-effects of immunosuppressive drugs, which may affect the long-term graft and patient outcomes.


  Conclusion Top


Steroid-free, calcineurin-free immunosuppressive protocol is a suitable choice for low immunological risk renal transplant recipients, but with a close and strict follow-up plan to avoid and treat any unwanted events. Adopting steroid-free, calcineurin-free regimens should be accompanied with protocol biopsy assessment to discover any histopathological abnormalities even before they are clinically detectable. Applying this protocol should be restricted mainly to the low immunological risk category, and we expect them to be perfectly controlled by lower levels of immunosuppression.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Lechler RI et al. Organ transplantation − how much of the promise has been realized? Nat Med 2005; 11:605–613.  Back to cited text no. 1
    
2.
Halloran PF. Immunosuppressive drugs for kidney transplantation. N Engl J Med 2004; 351:2715–2729.  Back to cited text no. 2
    
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4.
Wong W, Venetz JP, Tolkoff-Rubin N, Pascual M. 2005 immunosuppressive strategies in kidney transplantation: which role for the calcineurin inhibitors? Transplantation 2005; 80:289–296.  Back to cited text no. 4
    
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Hricik DE, Knauss TC, Bodziak KA, Weigel K, Rodriguez V, Seaman D et al. Withdrawal of steroid therapy in African American kidney transplant recipients receiving sirolimus and tacrolimus. Transplantation 2003; 76:938–942.  Back to cited text no. 5
    
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Nankivell BJ, Borrows RJ, Fung CL, O’Connell PJ, Chapman JR, Allen RD. Calcineurin inhibitor nephrotoxicity: longitudinal assessment by protocol histology. Transplantation 2004; 78:557–565.  Back to cited text no. 6
    
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Lemieux I, Houde I, Pascot A, Lachance JG, Noel R, Radeau T et al. Effects of prednisone withdrawal on the new metabolic triad in cyclosporine-treated kidney transplant patients. Kidney Int 2002; 62:1839–1847.  Back to cited text no. 7
    
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Cibrik D, Silva HT Jr., Vathsala A, Lackova E, Cornu-Artis C et al. Randomized trial of everolimus-facilitated calcineurin inhibitor minimization over 24 months in renal transplantation. Transplantation 2013; 95:933–942.  Back to cited text no. 8
    
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Chadban SJ, Eris JM, Kanellis J, Pilmore H, Lee PC, Lim SK et al. A randomized, controlled trial of everolimus-based dual immunosuppression versus standard of care in de novo kidney transplant recipients. Transpl Int 2014; 27:302–311.  Back to cited text no. 9
    
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Meier-Kriesche HU, Li S, Gruessner RW, Fung JJ, Bustami RT, Barr ML et al. Immunosuppression: evolution in practice and trends, 1994-2004. Am J Transplant 2006; 6(Part 2):1111–1131.  Back to cited text no. 11
    
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Nematalla AH, Bakr MA, Gheith OA, Elagroudy AE, Elshahawy el M, Aghoneim M. Steroid-avoidance immunosuppression regimen in live-donor renal allotransplant recipients: a prospective, randomized, controlled study. Exp Clin Transplant 2007; 5:673–679.  Back to cited text no. 12
    
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Sharif A, Baboolal K. Complications associated with new-onset diabetes after kidney transplantation. Nat Rev Nephrol 2012; 8:34–42.  Back to cited text no. 13
    
14.
Woodle ES, First MR, Pirsch J, Shihab F, Gaber AO, Van Veldhuisen P. A prospective, randomized, double-blind, placebo-controlled multicenter trial comparing early (7 day) corticosteroid cessation versus long-term, low-dose corticosteroid therapy. Ann Surg 2008; 248:564–577.  Back to cited text no. 14
    
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Kasiske BL, Zeier MG, Chapman JR, Craig JC, Ekberg H, Garvey CA et al. KDIGO clinical practice guideline for the care of kidney transplant recipients: a summary. Kidney Int 2010; 77:299–311.  Back to cited text no. 15
    
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Yan HL, Zong HT, Cui YS, Li N, Zhang Y. Calcineurin inhibitor avoidance and withdrawal for kidney transplantation: a systematic review and meta-analysis of randomized controlled trials. Transplant Proc 2014; 46:1302–1313.  Back to cited text no. 16
    
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Moore J, Ramakrishna S, Tan K, Cockwell P, Eardley K, Little MA et al. Identification of the optimal donor quality scoring system and measure of early renal function in kidney transplantation. Transplantation 2009; 87:578–586.  Back to cited text no. 17
    
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Zeier M, Van Der Giet M. Calcineurin inhibitor sparing regimens using m-target of rapamycin inhibitors: an opportunity to improve cardiovascular risk following kidney transplantation? Transpl Int 2011; 24:30–42.  Back to cited text no. 18
    
19.
Weir MR, Mulgaonkar S, Chan L, Shidban H, Waid TH, Preston D, Kalil RN et al. Mycophenolate mofetil-based immunosuppression with sirolimus in renal transplantation: a randomized, controlled Spare-the-Nephron trial. Kidney Int 2011; 79:897–907.  Back to cited text no. 19
    
20.
Rivelli RF, Goncalves RT, Leite M Jr., Santos MA, Delgado AG, Cardoso LR et al. Early withdrawal of calcineurin inhibitor from a sirolimus-based immunosuppression stabilizes fibrosis and the transforming growth factor-β signalling pathway in kidney transplant. Nephrology (Carlton) 2015; 20:168–176.  Back to cited text no. 20
    
21.
Vincenti F, Schena FP, Paraskevas S, Hauser IA, Walker RG, Grinyo J et al. A randomized, multicenter study of steroid avoidance, early steroid withdrawal or standard steroid therapy in kidney transplant recipients. Am J Transplant 2008; 8:307–316.  Back to cited text no. 21
    
22.
Heilman RL, Younan K, Wadei HM, Mai ML, Reddy KS, Chakkera HA et al. Results of a prospective randomized trial of sirolimus conversion in kidney transplant recipients on early corticosteroid withdrawal. Transplantation 2011; 92:767–773.  Back to cited text no. 22
    


    Figures

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    Tables

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