|Year : 2019 | Volume
| Issue : 2 | Page : 118-121
Use of everolimus as an alternative to calcineurin inhibitors in renal allograft recipients: A single South Indian center's experience
Manns Manohar John, Mahesh Eswarappa, Gurudev K Chennabasappa, Gireesh M Siddiah, R Rajashekar, Vivek Gaurav
Department of Nephrology, Ramaiah Medical College and Hospitals, Bengaluru, Karnataka, India
|Date of Submission||09-Nov-2018|
|Date of Acceptance||01-Feb-2019|
|Date of Web Publication||28-Jun-2019|
Dr. Mahesh Eswarappa
Department of Nephrology, Ramaiah Medical College and Hospitals, Bengaluru, Karnataka
Source of Support: None, Conflict of Interest: None
Introduction: Chronic Renal Allograft Injury(CRAI) is the most important cause of chronic graft dysfunction and loss. Calcineurin inhibitors (CNI) have been the back bone for immunosuppressive therapy, but their adverse effects can directly contribute to CRAI and compromise long-term renal allograft outcomes. Hence alternatives for CNI's such as Everolimus have been tried. Methods: Thirty de novo renal transplant patients who are receiving Everolimus as a part of their immunosuppressive regimen were included in this study. These patients were followed up for a period of 2 years. The primary outcome measures were creatinine clearance and the proportion of patients with biopsy proven acute rejection (BPAR). Results: Twenty three out of thirty patients were men. Follow up after initiation of everolimus the minimum duration was 2 years and maximum was of 5 years. There was a statically significant reduction in creatinine and improvement in GFR after initiation of everolimus to 3rd month of therapy and the reduction was consistent throughout the period of follow up which is for 24 months. Incidence of biopsy proven acute rejection (BPAR) was 16.7 %. Incidence of NODAT (New Onset Diabetes After Transplant) was 16.7. None of the patients had nephrotic range of proteinuria. Conclusions: Our study clearly shows use of everolimus is associated with improvement and subsequent stabilisation of graft function after switching over from CNI, without increased risk of BPAR and is associated with fewer adverse effects. Everolimus is a promising agent which can be used as an alternative/ additive agent in our immunosuppressive drugs regimens.
Keywords: Calcineurin inhibitors, everolimus, rejection, renal transplant
|How to cite this article:|
John MM, Eswarappa M, Chennabasappa GK, Siddiah GM, Rajashekar R, Gaurav V. Use of everolimus as an alternative to calcineurin inhibitors in renal allograft recipients: A single South Indian center's experience. Indian J Transplant 2019;13:118-21
|How to cite this URL:|
John MM, Eswarappa M, Chennabasappa GK, Siddiah GM, Rajashekar R, Gaurav V. Use of everolimus as an alternative to calcineurin inhibitors in renal allograft recipients: A single South Indian center's experience. Indian J Transplant [serial online] 2019 [cited 2019 Sep 15];13:118-21. Available from: http://www.ijtonline.in/text.asp?2019/13/2/118/261849
| Introduction|| |
Recent advances over the past decade in immunosuppressive therapy has resulted in considerable improvement in short-term renal allograft outcomes, but the improvements in long-term renal allograft outcomes have been little. Chronic renal allograft injury (CRAI) is the most important cause of chronic graft dysfunction and loss. Factors which have been implicated in the development of CRAI are many, to name a few: donor age, acute rejection, vascular remodeling, and calcineurin inhibitor (CNI)-induced nephrotoxicity. It has been shown that the level of renal function is associated with the long-term renal allograft longevity.
The CNIs (cyclosporine A [CsA] and tacrolimus) have been the backbone for immunosuppressive therapy in renal allograft recipients owing to their ability to substantially reduce the risk of acute rejection. However, CNIs have nephrotoxic adverse effects that can directly contribute to CRAI and compromise long-term renal allograft outcomes. Hence, there has been strong research interest in developing immunosuppressive regimens that maintain efficacy for the prevention of acute rejection, without compromising long-term renal allograft outcomes.
Everolimus (Certican®; Novartis Pharma AG, Basel, Switzerland) is a proliferation signal inhibitor with potent immunosuppressive action. Everolimus, a novel immunosuppressant drug, inhibits the T-lymphocyte proliferative response to cytokine signals, thus complementing the inhibitory effect of cyclosporine on T-cell-dependent growth factors such as interleukin-2, and enhances its immunosuppressive action.,
In renal transplantation, everolimus has showed comparable efficacy to mycophenolate mofetil (MMF) when used in combination with corticosteroids and standard-dose CsA for prevention of acute rejection., Studies in de novo renal transplant patients have clearly shown that the use of everolimus allows for early halving of CNI dose and better maintaining of renal function compared to full-dose CNI regimen. Hence, we reviewed the data of our renal transplant recipients who are on everolimus and studied the renal outcomes and side effect profile in an attempt to generate our own data which looks into the usefulness and side effect profile of everolimus in our South Indian population.
This is a retrospective, single-centered, noncomparative study done from November 2016 to April 2017. Data from 30 renal transplant recipient patients who are on everolimus at our center were included in this study. The study protocol was approved by the institution's Ethical Committee.
| Materials and Methods|| |
Thirty de novo renal transplant patients who are receiving everolimus as a part of their immunosuppressive regimen were included in this study. Data were obtained through the hospital medical electronic database system, and patients were periodically reviewed in outpatient follow-up clinic. These patients were followed up for a period of 2 years. All the patients were on triple immunosuppression-based regimen which included corticosteroid, MMF, and everolimus.
Patients' baseline demographic data were obtained. The primary outcome measures were creatinine clearance, estimated using the Chronic Kidney Disease-Epidemiology Collaboration formula, and the proportion of patients with biopsy-proven acute rejection (BPAR). The secondary outcome measures were the proportion of patients with death with a functioning graft, graft loss, treated presumed acute rejections, serious infections, and everolimus-related adverse effects.
Everolimus trough levels were monitored at hospital laboratory using microparticle enzyme immunoassay on IMX automated immunoassay analyzer at regular intervals and after change in the dosage.
Data were analyzed using SPSS Inc. Released 2009. PASW Statistics for Windows, Version 18.0. SPSS Inc., Chicago, IL, USA. Descriptive data of creatinine were analyzed and summarized in terms of mean and standard deviation (SD); normality of the data was checked using Shapiro test. Repeated measures ANOVA was used for comparing the creatinine levels at different time periods. P < 0.05 was considered statistically significant for analysis.
The inclusion criteria of this study were as follows:
- All renal transplant patients who were shifted to everolimus from CNIs as a part of maintenance immunosuppressive regimen in view of creeping creatinine
- At least 3 months into taking everolimus
- Minimum follow-up of 2 years from the date of start of everolimus.
The exclusion criteria of this study were as follows:
- Less than 3 months of everolimus intake
- Incomplete data and noncompliant patients.
The primary outcome of this study was to look for the beneficial renal effects of mammalian target of rapamycin (mTOR) inhibitors compared to CNIs and to study the complicated profile of mTOR inhibitors in our South Indian population.
Statistical methods were done using institutional SPSS software expressed as mean/median plus or minus SD.
| Results|| |
Twenty-three out of thirty patients were men (23%–76.7%) [Table 1]. The age group of patients ranged from 24 to 66 years with a mean age being 42.5 ± 9.8 years. From the date of renal transplant, the minimum time to start everolimus was 3 months with the maximum time being 51 months with a mean duration interval of 15 months. In terms of follow-up after initiation of everolimus, the minimum duration was 2 years and maximum was of 5 years.
Fifteen patients received no induction therapy (50%), 13 patients (43.3%) received induction with basiliximab, and 2 patients (6.7%) received induction with antithymocyte globulin [Table 2]. The serum creatinine and glomerular filtration rate (GFR) at the start of everolimus ranged from minimum of 1.2 mg/dL and 41.2 mL/min, respectively, to maximum of 2.2 mg/dL and 62.3 mL/min, respectively, with a mean value of 1.59 ± 0.27 mg/dL and 48.4 ± 5.6 mL/min. Subsequently, at the end of the 3rd month after initiating everolimus, the creatinine and GFR ranged from minimum of 1.1 mg/dL and 46.5 mL/min, respectively, to maximum of 1.8 mg/dL and 67.2 mL/min, respectively, with a mean value of 53.2 ± 6.6 mL/min. The difference in the mean value of GFR from the day of initiation till at the end of the 3rd month was 4.8 mL/min, and the mean drop in creatinine was 0.4 mg/dL (P < 0.05) [Table 3].
At the end of the 6th month after initiating everolimus therapy, the GFR ranged from minimum of 45.4 mL/min to maximum of 68.2 mL/min with a mean value of 53.3 ± 6.9 mL/min. The difference in the mean value of GFR was 4.9 mL/min at the end of the 6th month. At the end of the 12th month after initiating everolimus, the GFR ranged from minimum of 44.9 mL/min to maximum of 65.9 mL/min with a mean value of 51.9 ± 7 mL/min. The difference in the mean value of GFR was 3.5 mL/min at the end of the 12th month. At the end of the 24th month after initiating everolimus, the GFR ranged from minimum of 45.1 mL/min to maximum of 66.2 mL/min with a mean value of 52.5 ± 6.9 mL/min. The difference in the mean value of GFR was 4.1 mL/min at the end of the 24th month, and drop in creatinine was 0.37 mg/dL. There was a statically significant reduction in creatinine and improvement in GFR after initiation of everolimus to the 3rd month of therapy, and the reduction was consistent throughout the period of follow-up which is for 24 months.
The mean BP of patients after 1 year after starting everolimus was systolic blood pressure (BP) of 134 ± 14.2 mmHg with diastolic BP of 88 ± 9.6 mmHg. However, no patient developed hypertension after initiation of everolimus.
Dosage of everolimus ranged from minimum of 0.5 mg to maximum of 1.5 mg/day with a mean dose of 0.85 ± 0.22 mg/day. Dosage of MMF ranged from minimum of 1.5 g to maximum of 2 g/day with a mean dose of 1.6 ± 0.2 g/day. The everolimus drug level ranged from minimum of 2.1 ng/mL to maximum of 6.31 ng/mL with a mean value of 4.2 ± 0.95 ng/mL.
Incidence of BPAR was 16.7% (5 patients) [Table 4]. Three out of those five patients had not received induction therapy. Incidence of BPAR was high within the first 6 months of transplant, and 4 out of 5 patients had BPAR within the first 6 months of renal transplant. The mean interval of development of BPAR after initiating everolimus was 3.5 ± 0.8 months.
Four out of five BPARs were acute cell-mediated rejection which responded well to pulse intravenous (IV) steroids. One patient had acute antibody-mediated rejection requiring pulse IV steroids with five sessions of plasma exchange following which serum creatinine of the patient maintained between 1.8 and 2.0 mg/dL. All five patients with BPAR were continued on everolimus.
Incidence of new-onset diabetes after transplant (NODAT) was 16.7% (5 patients); they were managed with regular insulin for initial period of time and later switched to oral drugs.
The mean level of proteinuria prior to initiation of everolimus was 226.04 ± 114 mg/day. The level of proteinuria at the end of 6 months of everolimus treatment increased to 886.28 ± 248.8 mg/day. None of the patients had nephritic range of proteinuria.
The mean level of serum cholesterol and triglycerides after 6 months of everolimus was 205.13 ± 24.3 and 172.13 ± 24.3 mg/dL, respectively.
None of the patients had a significant thrombocytopenia in our study. The mean platelet count was 177690 ± 110394 cells/mm3 of blood.
| Discussion|| |
The use of everolimus in our study had favorable outcomes in terms of improvement and subsequent stabilization of graft function. Our study results are in concordance with the Argentina National Registry data and CONCEPT and ZEUS study which showed improvement in graft function after switching from CNI to everolimus. In CONCEPT, kidney transplant recipients switched from CsA to sirolimus at 3 months or remained on a CsA-based regimen. In the Intention to treat (ITT) and on-treatment populations, the mean between-group difference in estimated GFR (eGFR) (Cockcroft-Gault) was 4.5 ml/min (P = 0.013) and 9.9 ml/min (P = 0.002), respectively. In the ZEUS trial, conversion from CsA to everolimus took place at 4.5 months, and the mean difference in eGFR (Nankivell) between groups was 7.5 ml/min/1.73 m2 and 13.8 ml/min/1.73 m2 for the ITT and on-treatment populations (both P < 0.001).
The optimal timing for reduction or elimination of the CNI and introduction of everolimus is not clear, but early commencement is associated with an improvement in eGFR before the occurrence of structural renal damage caused by CNI toxicity. In our study, the mean time from the renal transplant to commencement of everolimus was 15 months.
Incidence of BPAR was 16.7% (5 patients). Three out of those five patients had not received induction therapy. Incidence of BPAR was high within the first 6 months of transplant; four out of five patients had BPAR within the first 6 months of renal transplant. The incidence of BPAR in everolimus-based regimen is almost similar to the incidence of BPAR in CNI-based regimen at our center. It is notable that the 12-month incidence of BPAR was not significantly higher in the mTOR inhibitor treatment group in either the CONCEPT study or the ZEUS study.
The mean BP of patients after 1 year after starting everolimus was systolic BP of 134 ± 14.2 mmHg with diastolic BP of 88 ± 9.6 mmHg. However, no patient developed hypertension after initiation of everolimus. Our results are almost similar to Argentina National Registry data which showed that hypertension did not increase significantly at 12 months.
When we compared the side effect profile of everolimus, we did not observe any new occurrence of malignancy; the incidence of hypertension was 0. Incidence of NODAT was 16.7% (5 patients), and they were managed with regular insulin. The mean level of proteinuria prior to initiation of everolimus was 226.04 ± 114 mg/day. The level of proteinuria at the end of 6 months of everolimus treatment increased to 886.28 ± 248.8 mg/day. None of the patients had nephrotic range of proteinuria. There are very few studies which have looked into the effect of everolimus on proteinuria; in a study done by Tedesco-Silva et al., proteinuria (determined by a spot urine protein/creatinine ratio) was detected in <5% of patients.
The mean level of serum cholesterol and triglycerides after 6 months of everolimus was 205.13 ± 24.3 and 172.13 ± 24.3 mg/dL, respectively; in a study done by Andrés et al., everolimus use was associated with increase in serum cholesterol and triglyceride levels.
None of the patients had a significant thrombocytopenia in our study. The mean platelet count was 177690 ± 110394 cells/mm3 of blood.
| Conclusions|| |
Evidence from clinical trials supports the efficacy and tolerability of everolimus in renal transplant recipients. Notably, clinical trial data indicate that everolimus can facilitate CNI minimization/halving without compromising efficacy. Our study clearly shows that the use of everolimus is associated with improvement and subsequent stabilization of graft function after switching over from CNI, without increased risk of BPAR, and is associated with fewer adverse effects. Everolimus is a promising agent which can be used as an alternative/additive agent in our immunosuppressive drug regimens.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Meier-Kriesche HU, Schold JD, Srinivas TR, Kaplan B. Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era. Am J Transplant 2004;4:378-83.
Chapman JR, O'Connell PJ, Nankivell BJ. Chronic renal allograft dysfunction. J Am Soc Nephrol 2005;16:3015-26.
Hariharan S, McBride MA, Cherikh WS, Tolleris CB, Bresnahan BA, Johnson CP, et al.
Post-transplant renal function in the first year predicts long-term kidney transplant survival. Kidney Int 2002;62:311-8.
Nankivell BJ, Borrows RJ, Fung CL, O'Connell PJ, Chapman JR, Allen RD, et al.
Calcineurin inhibitor nephrotoxicity: Longitudinal assessment by protocol histology. Transplantation 2004;78:557-65.
Schuler W, Sedrani R, Cottens S, Häberlin B, Schulz M, Schuurman HJ, et al.
SDZ RAD, a new rapamycin derivative: Pharmacological propertiesin vitro
and in vivo
. Transplantation 1997;64:36-42.
Nashan B. Early clinical experience with a novel rapamycin derivative. Ther Drug Monit 2002;24:53-8.
Serkova N, Hausen B, Berry GJ, Jacobsen W, Benet LZ, Morris RE, et al.
Tissue distribution and clinical monitoring of the novel macrolide immunosuppressant SDZ-RAD and its metabolites in monkey lung transplant recipients: Interaction with cyclosporine. J Pharmacol Exp Ther 2000;294:323-32.
Lorber MI, Mulgaonkar S, Butt KM, Elkhammas E, Mendez R, Rajagopalan PR, et al.
Everolimus versus mycophenolate mofetil in the prevention of rejection in de novo
renal transplant recipients: A 3-year randomized, multicenter, phase III study. Transplantation 2005;80:244-52.
Vítko S, Margreiter R, Weimar W, Dantal J, Kuypers D, Winkler M, et al.
Three-year efficacy and safety results from a study of everolimus versus mycophenolate mofetil in de novo
renal transplant patients. Am J Transplant 2005;5:2521-30.
Vitko S, Tedesco H, Eris J, Pascual J, Whelchel J, Magee JC, et al.
Everolimus with optimized cyclosporine dosing in renal transplant recipients: 6-month safety and efficacy results of two randomized studies. Am J Transplant 2004;4:626-35.
Cicora F, Massari P, Acosta F, Petrone H, Cambariere R, González I, et al.
Use of everolimus in renal transplant recipients: Data from a national registry. Transplant Proc 2014;46:2991-5.
Lebranchu Y, Thierry A, Thervet E, Büchler M, Etienne I, Westeel PF, et al.
Efficacy and safety of early cyclosporine conversion to sirolimus with continued MMF-four-year results of the postconcept study. Am J Transplant 2011;11:1665-75.
Budde K, Lehner F, Sommerer C, Arns W, Reinke P, Eisenberger U, et al.
Conversion from cyclosporine to everolimus at 4.5 months posttransplant: 3-year results from the randomized ZEUS study. Am J Transplant 2012;12:1528-40.
Gurk-Turner C, Manitpisitkul W, Cooper M. A comprehensive review of everolimus clinical reports: A new mammalian target of rapamycin inhibitor. Transplantation 2012;94:659-68.
Tedesco-Silva H Jr., Vitko S, Pascual J, Eris J, Magee JC, Whelchel J, et al.
12-month safety and efficacy of everolimus with reduced exposure cyclosporine in de novo
renal transplant recipients. Transpl Int 2007;20:27-36.
Andrés V, Castro C, Campistol JM. Potential role of proliferation signal inhibitors on atherosclerosis in renal transplant patients. Nephrol Dial Transplant 2006;21 Suppl 3:iii14-7.
[Table 1], [Table 2], [Table 3], [Table 4]