|Year : 2015 | Volume
| Issue : 6 | Page : 1294-1299
|Everolimus with low-dose cyclosporine in de novo renal transplant recipients: A single center Indian experience
Sailaja Kesiraju1, Uma Maheswara Rao2, Purna Paritala3, VS Reddy3, S Sahariah4
1 Transimmun-Transplantation Immunology and Research Center, Somajiguda, Hyderabad, India
2 Kidney Transplantation Unit, Mahavir Hospital and Research Center, AC Guards, Hyderabad, India
3 Department of Nephrology and Transplantation, Krishna Institute of Medical Sciences, Hyderabad, India
4 Transimmun-Transplantation Immunology and Research Center, Somajiguda; Kidney Transplantation Unit, Mahavir Hospital and Research Center, AC Guards; Department of Nephrology and Transplantation, Krishna Institute of Medical Sciences, Hyderabad, India
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|Date of Web Publication||30-Oct-2015|
|How to cite this article:|
Kesiraju S, Rao UM, Paritala P, Reddy V S, Sahariah S. Everolimus with low-dose cyclosporine in de novo renal transplant recipients: A single center Indian experience. Saudi J Kidney Dis Transpl 2015;26:1294-9
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Kesiraju S, Rao UM, Paritala P, Reddy V S, Sahariah S. Everolimus with low-dose cyclosporine in de novo renal transplant recipients: A single center Indian experience. Saudi J Kidney Dis Transpl [serial online] 2015 [cited 2021 Oct 20];26:1294-9. Available from: https://www.sjkdt.org/text.asp?2015/26/6/1294/168679
Current immunosuppressive drug regimens have appreciably improved short-term outcomes following renal transplantation. However, there has been no significant improvement in long-term graft survival.  The number of factors attributing this are donor-related and recipient-related, in addition to factors related to the safety, tolerability and compliance with immunosuppressive regimens.  It is known that the level of renal function is associated with the longevity of a renal allograft.  Calcineurin inhibitors (CNIs) diminish the rate of acute rejection; however, use of CNIs causes nephrotoxicity, eventually resulting in chronic graft dysfunction.  Because renal function at 12 months post-transplant potentially predicts long-term graft function, , optimizing renal function early is important. Therefore, it is vital to have immunosuppressive regimens that provides for early CNI minimization to reduce CNI-related nephrotoxicity, while at the same time maintaining the current low acute rejection rate. ,
This seems to be presently possible with the use of new immunosuppressive drugs such as everolimus,  a novel immunosuppressant drug that inhibits the T-lymphocyte proliferative response to cytokine signals thus complementing the inhibitory effect of cyclosporine on T-celldependent growth factors such as interleukin (IL)-2 and enhances its immunosuppressive action. ,,,, Studies have shown that when cyclosporine is given in association with everolimus, the risk of acute rejection is related to low everolimus blood levels rather than to cyclosporine blood levels.  Therefore, if everolimus doses are kept adequate, cyclosporine doses could be reduced without compromising efficacy. ,,,, Other studies have also shown that patients given a sufficient everolimus dose to obtain much higher trough levels of 8-12 ng/mL and very low dose cyclosporine (67% reduction of C2 levels) had a significantly better probability of graft survival. ,
Results of these studies encouraged us to review and analyze the data of de novo renal transplant recipients at our institute who were administered everolimus with low-dose cyclosporine. We present here the results from this retrospective study designed to evaluate the safety and efficacy of this regime.
This was a retrospective, non-comparative, single-center study conducted between November 2011 and March 2012. Data of all the patients who received a single kidney transplant from a deceased or living donor, from January 2006 to January 2007 at our center, were included in this study. The study protocol was approved by the institute's ethical committee and the study was conducted in compliance with the provisions of the Declaration of Helsinki and Good Clinical Practice guidelines.
We reviewed data for 26 patients (19 males, 7 females) in the age group of 21-46 years with a mean age of 36.8 years to evaluate the safety and efficacy of low-dose cyclosporine with everolimus in de novo renal transplant recipients. Data up to a five-year follow-up period were reviewed and analyzed. All the patients had received everolimus 1.5 mg (0.75 mg BD) + cyclosporine 200 mg (100 mg BD) and prednisolone 20 mg as initial therapy. At the end of the third month, the cyclosporine dose was brought down to 100 mg (50 mg BD), which was later further reduced to 50 mg (25 mg BD). Ten of 26 patients who had received deceased donor transplantation were administered two doses of 50 mg daclizumab (Zenapax, Roche Pharma) on Day 0 and on Day 14 post-operatively as induction therapy. Everolimus trough levels were monitored at a local laboratory using Microparticle Enzyme Immunoassay (MEIA) on (IMX Automated Immunoassay analyzer with System and TDM transplant modules -Abbott Diagnostics, USA) at regular intervals and after change in the dosage. All kidney transplant recipients received oral Valganciclovir for a period of three months and Cotrimoxazole for a period of six months post-transplantation as Cytomegalovirus CMV and Pneumocystis carinii pneumonia prophylaxis. Prednisone was initiated on Day 1 and then gradually tapered to a dose of 5 mg/day.
Data collected for one-year duration (January 2006 to January 2007) were considered as the core study data. Data up to the five-year follow-up period in the patient's assigned treatment were evaluated. Data for adverse events, rejection episodes and opportunistic infections were collected. In addition to these, data of urine protein and spot urine protein/ creatinine ratio, hemogram, lipid profile and liver function tests were also evaluated. Acute rejections (ARs), reported during the followup period, were treated with intravenous methyl prednisolone.
The primary outcome measures were creatinine clearance (CrCl), estimated using the Cockcroft-Gault (mL/min/1.73 m 2 ) formula, and the proportion of patients with biopsyproven acute rejection (BPAR). Secondary outcome measures were the proportion of patients with graft loss, death and treated ARs.
Safety assessments included the frequency of deaths, serious adverse events (AEs), early discontinuations, malignancies and infections. Serial laboratory results and proportions of patients with clinically notable abnormalities were evaluated. Renal function was assessed with creatinine levels and CrCl.
The quantitative variables were expressed as mean and standard deviation. P-values <0.05 were considered statistically significant. Microsoft Excel was used for the analysis.
Of 26 patients considered for review, three had an early graft loss, two were switched to other therapies and one patient was lost to follow-up. The patient survival rate was 88.5% (23/26). Graft loss was due to death with functioning graft in three patients and one each of liver failure following viral hepatitis, pulmonary aspergillosis and cardiovascular disease. Two patients were switched over to other protocols due to progressive renal dysfunction. Data from 20 patients were evaluated from the six-month time point onwards.
The BPAR rate was 15%, occurred during the third month in two patients and in the second year in one patient. All the episodes were reversible with intravenous methyl prednisolone. The mean (SD) serum creatinine levels at six months was 1.5 (0.5) mg/dL, which went up insignificantly to 1.7 (0.4) mg/ dL at Year 5. The mean (SD) 6-month CrCl in patients with functioning grafts was 66.7 (11.8) mL/min, which significantly came down to 60.4 (10.8), 56.1 (8.6), 51.7 (10.1), 48.9 (9.6) and 45.6 (10.0) mL/min at the 1-, 2-, 3-, 4and 5year follow-up periods, respectively [Figure 1]. The mean (SD) everolimus trough levels were 9.1 (3.1) ng/mL at the 6-month time point, but came down to the target levels of 3- 8 ng/mL at 1-year follow-up. The mean (SD) everolimus trough levels at the 1-, 2-, 3 and 4- year follow-up periods were 7.2 (2.8), 5.5 (2.5), 4.8 (1.3) and 3.4 (1.4) ng/mL, respectively. The everolimus trough levels further came down to <3.0 ng/mL at the 5-year follow-up, and were at 2.9 (0.9) ng/mL. Change in everolimus trough levels from the 6 th month onwards was statistically significant (P = 0.000; 95 CI) [Figure 2]A. Cyclosporine doses were reduced over a period of 6 months, maintaining the C-2 levels at 550-650 (6 months) and 150-250 (5 years) ng/mL. The mean (SD) cyclosporine C-2 level at 6 months was 543 (182.7) ng/mL, which significantly came down to 406.2 (124.4), 331.9 (119.6), 243.9 (106.3), 175.6 (52.6) and 167.0 (49.7) ng/mL at the 1-, 2-, 3and 4and 5-year follow-up periods, respectively [Figure 2]B.
|Figure 2: (A) Mean (SD) everolimus trough levels and (B) mean (SD) cyclosporine C-2 levels over the period of 5 years.|
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Hyperlipidemia was observed in seven (33.3%) of the patients, and they were treated with statins. The 6-month and 1-year serum cholesterol levels were 210.2 (53.1) and 193.4 (45.7) mg/dL, respectively. Cholesterol levels came down significantly to 156.2 (16.1) and 151.7 (15.8) mg/dL at the 3and 5-year follow-up periods. Liver function was normal in all patients except one who had chronic hepatitis. High levels of proteinuria were observed in 12.5% of the patients between 6 months and 1year post-transplantation, and were at 331.6 (148.2) and 396.1 (119.7) mg/dL, respectively. The mean (SD) proteinuria levels came down to 298.1 (89.6) mg/dL at 3 years, but went up again to 305.5 (104.3) mg/dL at the 5-year follow-up [Figure 3]. The mean spot urinary protein/creatinine ratio was 0.87 at 6 months and reduced to 0.48 at 1 year. There was no nephritic-range proteinuria noted in this cohort of patients.
Details of AEs are presented in [Table 1]. AEs reported were minimal in this study group. Incidences of infections were 45%, with urinary tract infection being most frequently reported and E. coli being the most commonly isolated organism. One (5%) incidence each of gingival hyperplasia, leukopenia, post-transplant diabetes mellitus and thrombocytopenia were also reported.
The key challenge in renal transplantation is the reduction or avoidance of CNIs, thereby reducing CNI-related morbidity. But, these efforts were limited by an increase in acute rejections. , Although some investigators have warned against discarding CNIs, , it is beyond doubt that a minimization in CNI dosage is desirable for reducing CNI-related morbidity. The synergetic interaction between cyclosporine and everolimus provides the rationale to reduce the doses of cyclosporine. ,,, In this retrospective study, we evaluated the efficacy and safety of everolimus combined with low doses of cyclosporine.
Our study demonstrated that everolimus allowed rapid reduction of cyclosporine in the early post-transplantation period, avoiding nephrotoxicity and CNI-related AEs without an increased risk of rejection. Everolimus with low-dose cyclosporine in this group of patients helped in reducing the BPARs. The BPAR rate of 15% in our study was comparable to BPAR rates of 25.9% and 13.7%  and 14.7%  with 1.5 mg everolimus and BPAR rates of 19.2% and 15.8% and 11.9% with 3 mg everolimus reported in pivotal trials. ,, Earlier studies showed that patients receiving everolimus with standard cyclosporine exposure display worse renal function at the end of the first year.  Study A2309 showed that higher estimated glomerular filtration rate (eGFR) at 12 months with the everolimus 1.5 mg regimen was associated with improvement in long-term graft function.  In the present study group, 85% of the patients attained >55 mL/min eGFR within 6 months post-transplantation, which persisted over 18 months, leading to the long-term outcome. Previous studies addressing the issue of giving very low-dose cyclosporine in association with high-dose everolimus, with eGFR as the primary end point, failed to demonstrate a higher eGFR with very low dose cyclosporine because of poor investigator compliance with cyclosporine dosing.  In contrast to this study, in our study group, cyclosporine as well as everolimus blood levels were maintained in the target range throughout the follow-up.
The most prevalent AEs with mTOR inhibitors were delayed wound healing, higher lymphocele rate, hematological problems, hyperlipidemia and proteinuria, which were all attributed to its anti-proliferative effects. In the present study group, the rate of AEs was minimal. This was achieved by maintaining the everolimus trough levels between 3 and 8 ng/mL and later to ≤3 ng/mL and maintaining the cyclosporine C-2 levels at ≤200 ng/mL. There was no delayed wound healing and lymphoceles or delayed graft function in this cohort of patients. A well-known side-effect of everolimus is higher cholesterol levels. In the present study group, hypercholesterolemia and hypertriglyceridemia peaked at 3-4 months post-transplantation.
Proteinuria, a well-known complication of mTor inhibitors, is a relevant concern, as it can be associated with a pathologic pattern of focal segmental glomerulosclerosis. , Studies have documented that everolimus-treated patients presented a transient increase of proteinuria immediately after transplantation, with the highest level 15 days after transplantation.  However, in our patient cohort, there was mild proteinuria, except in three patients who excreted more than 500 mg/day and never reached the sub-nephrotic or nephritic levels. This study has some important limitations. First, this retrospective analysis may be subjected to flaws inherent to the nature of registry databases, such as reporting bias or error. Other limitations of this retrospective study are smaller cohort and absence of any control group. But, the results from this study are in line with outcomes demonstrated in extensive clinical trials and comparable with our regular regimen of triple-drug therapy.
In conclusion, our data confirm the efficacy and safety of everolimus with low-dose cyclosporine and CNI minimization. The lowdose cyclosporine with everolimus and prednisolone combination in de novo live and deceased donor renal transplant recipients was found to be suitable for sustaining long-term graft function with minimal AEs. Notably, the use of everolimus enabled reduced exposure to cyclosporine, resulting in improved renal function with no increase in the risk of acute rejection.
Conflict of interest: None declared.
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Dr. Sailaja Kesiraju
Transimmun-Transplantation Immunology and Research Center, Somajiguda, Hyderabad
[Figure 1], [Figure 2], [Figure 3]
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