| Abstract|| |
Chronic allograft nephropathy (CAN) is a major cause of late kidney allograft loss. Everolimus, a novel proliferation signal inhibitor, ameliorates CAN by its antiproliferative or apoptosis-enhancing effects. This study aims to evaluate the safety and efficacy of everolimus in renal transplant recipients with calcineurin inhibitor (CNI) withdrawal either due to CAN or cal-cineurin inhibitor toxicity (CNIT). A total 21 patients with CAN or CNIT converted from CNI to everolimus were prospectively studied from 2006 to 2009. There were 19 males and two females, with a mean age of 32.9 ± 10.7 years. Eight patients had chronic interstitial nephritis, three had diabetes mellitus, nine had end-stage renal disease and one had focal segmental glomerulosclerosis as native kidney disease. The mean duration of dialysis was 10.7 ± 7 months. 57.2% of the patients had CAN and 42.8% had CNIT. Everolimus was started within six months of post-transplantation in six patients, within 6-12 months in two patients, within 1-2 years in four patients and after more than 2 years in nine patients. The mean dose at first month was 1.25 mg/day, at six month was 1.028 ± 0.3 mg/day and at 12 th month was 0.97 ± 0.2 mg/day, with a mean trough level of 6.35 ± 3 ng/dL, 5.18 ± 3 ng/dL and 6.43 ± 1.7 ng/dL, respectively. At the 12 th month, serum creatinine declined from 2.07 ± 0.58 mg/dL to 1.65 ± 0.81 mg/dL. The mean calculated glomerular filtration rate improved from 40.85 ± 8.8 mL/min to 56.84 ± 11.4 mL/min. No major side-effects were observed. Everolimus along with mycophenolate mofetil or azathioprine and prednisolone as a maintenance immunosuppressive therapy was found to be effective and safe in patients with CNIs withdrawal either due to CAN or CNIT.
|How to cite this article:|
Das U, Dakshinamurty KV. Safety and efficacy of everolimus in chronic allograft nephropathy. Saudi J Kidney Dis Transpl 2013;24:910-6
|How to cite this URL:|
Das U, Dakshinamurty KV. Safety and efficacy of everolimus in chronic allograft nephropathy. Saudi J Kidney Dis Transpl [serial online] 2013 [cited 2020 Feb 29];24:910-6. Available from: http://www.sjkdt.org/text.asp?2013/24/5/910/118074
| Introduction|| |
Chronic allograft dysfunction, which is also known as interstitial fibrosis/tubular atrophy (IF/TA) or chronic graft failure, is the second major cause of long-term graft failure. It is defined as functional and morphological deterioration of a renal allograft at least three to six months after transplantation. , The incidence is about 2-3% per year. Despite advances in immunosuppressive therapy for control of acute allograft rejection, the long-term renal transplantation outcome had not significantly improved over the last decade.  The causes of chronic allograft nephropathy (CAN) are multi-factorial. Calcineurin inhibitors (CNIs) have been a cornerstone of immunosuppression in solid organ transplantation since 1980, but have multiple side-effects including nephrotoxicity contributing to long-term allograft dysfunction.  Lowering the CNIs dose is associated with reduced nephrotoxicity.  Calcineurin inhibitor toxicity (CNIT) is characterized by fibrotic changes throughout the kidney allograft and may contribute to CAN. Current immunosuppressive regimens do not adequately address the cause of long-term allograft dysfunction. Reducing dose or withdrawing CNIs along with control of blood pressure (BP), dyslipidemia and blood sugar and taking undue care during cold and warm ischemic periods may prevent the progression or occurrence of CAN. At present, the clinical challenge is to develop immunosuppressive protocols to decrease the risk of losing the graft in the long term, while keeping the current low-rates of biopsy-proven acute rejection (BPAR).  Several studies claim that newer immunosuppressive agents allow reducing or withdrawing CNIs without much effect on graft survival. ,,,,,,,,,,,, Everolimus is a new proliferative signal inhibitor (PSI) that acts at a later stage of the cell cycle, blocking the proliferation signal provided by growth factors and preventing cells from entering the S phase.  Several clinical studies had shown that everolimus has a multifactorial approach to improve the long-term outcomes by facilitating CNI minimization and inhibiting smooth muscle proliferation. ,,,,,, We conducted this study to evaluate its efficacy and safety in CAN in our center.
| Patients and Methods|| |
This prospective, non-randomized, pilot observational study was carried out in our institute from January 2006 to December 2010. Patients with biopsy-proven CAN or CNIT, with no evidence of renal artery stenosis, with proteinuria less than 800 mg/day, without severe dyslipidemia, with no leucopenia, with no systemic infection, with no active or history of malignancy, who had given consent to participate were included in this study. The following baseline investigations were performed:
- Doppler ultrasound to exclude any mechanical or vascular problems.
- A kidney biopsy to define the histological changes (degree of IF, tubular and glomerular changes).
- A 24-h urine protein excretion.
- Echocardiography study.
The following parameters were monitored at every visit throughout the study period:
- Serum creatinine (SCr) levels and calculated glomerular filtration rate (cGFR) using the Modification of Diet in Renal Disease. GFR (MDRD) formula (mL/min/1.73 m 2 ) = 175 × (Scr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African American).
- Complete blood picture (CBP), cholesterol, high-density lipoprotein-cholesterol and triglyceride levels.
- BP measurements and the number of BP medications.
- Cholesterol-lowering medication requirement.
- 24-h urine protein excretion.
- Additional serum tests to measure uric acid, calcium, phosphorus, sodium, potassium and liver functions.
Demographic data were obtained for each patient together with the regimen and the dosages of immunosuppressive, lipid-lowering and antihypertension medications.
Graft biopsies were processed for both light microscopy (LM) and immunofluorescence (IF) as per the standard protocol. Slides were examined by the renal pathologist of the institute. CAN is defined as non-specific chronic changes including glomerulosclerosis, tubular atrophy and interstitial fibrosis and fibrointimal thickening of large- and medium-sized arteries, and is graded according to the Banff 97 classification system. CNIT was diagnosed if the biopsy showed tubular vacuolization, segmental arteriolopathy, arteriolar myocyte vacuolization and striped or diffuse interstitial fibrosis.  CAN is termed as interstitial fibrosis and tubular atrophy in the new Banff classification. 
A CNI tapering approach was used. The initial dose of everolimus was 0.75 mg twice daily for all patients. The dose was adjusted to achieve trough levels between 3 and 8 ng/mL. In parallel, the CNI dose was tapered and stopped over a 4-week period by performing 50% reduction on Day 1, 25% reduction over 1-3 weeks and discontinuation in the 4 th week.  We analyzed the pre-conversion values of different parameters versus those obtained at the end of the 6 th and 12 th months of the observation period. Basal everolimus plasma levels were determined by a fluorescence polarization immunoassay (FPIA) method (Innofluor Certican assay, Seradyn, IN, Indianapolis, USA) using a TDxFLx analyzer (Abbot, Japan). 
| Statistical Analysis|| |
A descriptive statistical analysis was performed, including means, standard deviation and/or range for each data end point using a Microsoft Excel data sheet. A paired sample test was applied to compare parameters in the pre- and post-conversion periods. P-value less than 0.05 was considered statistically significant.
| Results|| |
A total 30 patients with CAN or CNIT converted from CNI-based immunosuppressant to everolimus-based maintenance immunosuppressant were prospectively studied from January 2006 to March 2010. Nine patients were excluded (six patients had expired in the initial period and three patients were irregular on follow-up) from the study. Finally, 21 patients were included in the study. The mean age of the patients was 32.9 ± 10.7 years and 19 patients were male while two patients were female. The mean duration of dialysis was 10.7 ± 7 months. Native kidney diseases were as follows: Eight patients had chronic interstitial nephritis (CIN), three had diabetes mellitus (DM), nine had end-stage renal disease (ESRD) and one had focal segmental glomerulosclerosis (FSGS). Before conversion, eight (38%) patients had received cyclosporine, mycophenolate mofetil (MMF) and prednisolone as maintenance immunosuppressants and 13 (62%) patients had received cyclosporine, Azathioprine and prednisolone. The mean dose of MMF was 1500 mg/day and of Azathioprine was 70 mg/day. Donor types were as follows: Eight mothers, four deceased, two siblings, three wives and three fathers. Five patients were HCV positive and four patients were HBV positive. Twelve patients (57.2%) had CAN and nine (42.8%) had CNIT as indications for conversion. [Table 1] shows the period from the date of transplantation to the initiation of everolimus. Mean dose requirement at the first month was 1.25 ± 0.3 mg/day, at the 6 th month was 1.028 ± 0.3 mg/day and at the 12 th month was 0.97 ± 0.2 mg/day, with mean trough level of 6.35 ± 3 ng/L, 5.18 ± 3 ng/L and 6.43 ± 1.7 ng/L, respectively [Figure 1].
|Table 1: Period in months from transplantation to initiation of everolimus.|
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|Figure 1: Mean doses and trough level of everolimus blood concentration.|
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At the 6 th month, the SCr declined from 2.07 ± 0.58 to 1.735 ± 0.67 mg/dL (P-value = 0.04) and at the 12 th month it declined to 1.65 ± 0.81 mg/dL (P-value = 0.1) [Figure 2]. The mean cGFR improved from 40.85 ± 8.8 mL/min (at baseline) to 50.21 ± 8.8 mL/min at the 6 th month (P-value = 0.01) and at 12 th month to 56.84 ± 11.4 mL/min (P-value = 0.0014) [Figure 3].
|Figure 2: Serum creatinine level of each patient at baseline, 6th month and 12th month of follow-up|
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|Figure 3: Calculated GFR of each patient at baseline and at the 12th month after conversion.|
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An increase in SCr level was sporadically observed in two patients whose baseline GFRs were less than 30 mL/min. Subsequently, one of them progressed to graft failure.
We did not observe any significant change in proteinuria, lipid profile, CBP and other biochemical parameters except reduction of serum potassium [Table 2]. There was no incidence of new-onset DM and no incidence of requirement of increase in antihypertensive drugs or lipid-lowering agents [Table 3]. There was no incidence of acute rejection (AR). The number of patients suffering from major infection during the study period was four (30.8%). Everolimus was stopped in one patient who had graft failure.
| Discussion|| |
Everolimus at doses of either 1.5 mg/day or 3 mg/day in association with cyclosporine and steroid has proven effective in preventing AR in de novo studies. ,,,,,,, Ongoing studies suggest that everolimus may affect the primary cause of CAN in the following ways: (1) allowing to reduce CNI dose, (2) inhibiting vascular remodeling through its antiproliferative and proapoptotic actions and (3) exerting anti-viral effects toward cytomegalovirus infection.  In experimental models, everolimus has proven capable of slowing CAN progression.  The present study is a preliminary short-term evaluation of conversion from CNIs to everolimus in renal transplant recipients with CAN.
In this study, we observed a significant improvement of graft function with everolimus-based immunosuppressant with CNI withdrawal. All clinical studies with different everolimus protocols with CNI minimization or CNI withdrawal in CAN or de novo studies showed a significant improvement of cGFR and declining of SCr. ,,,,
There was no incidence of AR in the present study. Conversely, Pascual et al showed that the incidence of efficacy failure at the 12 th month was 28% where was everolimus used at 1.5-3 mg/day with reduced CNI.  Everolimus with a trough concentration of > 3 ng/mL is associated with a reduced incidence of BPAR and reduced graft loss compared with a trough level of <3 ng/mL.  In similar studies conducted by Ruiz et al and Giron et al, the incidence of AR was 2% and 14%, respectively [Table 4]. ,
Everolimus is usually associated with dose-related side-effects such as thrombocytopenia, leucopenia, hyperlipidimia, hypertension, proteinuria, infection, GI symptoms and mouth ulcer.  Different pilot studies concluded that everolimus at 0.75-1.5 mg/day in combination with reduced CSA provides low toxicity compared with a high dose with full CSA.  We did not observe any significant change in the lipid profile, proteinuria and hemopoietic system [Table 2]. Similarly, in our experience, conversion did not effect in the control of BP and blood sugar. In addition, there was no incidence of dermatological complication noted. Four patients experienced recurrent urinary tract infection (UTI), which was controlled eventually. They had vesicoureteral reflux (grade four) as native kidney disease. Except this, we did not come across any infection. These can be explained by the elimination of side-effects contributed by CNIs and requirement of a low dose of everolimus in our patients. Our study agrees with that of Giron and Morales [Table 4]. , Pascual et al had observed UTI and hyperlipidimia as the most frequent adverse effects involving 31% and 37.6% patients, respectively. Lymphocele and pneumonia were less frequent. They also observed a low incidence of hypertension and hyperlipidimia at 12 months in patients receiving a low dose (1.5 mg/day), which is in agreement with our study to some extent. 
Regarding pulmonary fibrosis, to the best of our knowledge, there is no case report in renal transplant recipients receiving everolimus. Similarly, the incidence of pneumonitis also is very low in clinical trials.  These complications were not seen in our patients. Wound healing problems did not arise in this study as it was used in late post-transplantation period.
Most of the patients (61%) in our study achieved target trough levels with 1 mg/day in the first week. Dose requirement had decreased by the end of the 6 th month, and further decreased at the 12 th month. In contrast to this, other studies required a higher dose of everolimus to maintain the recommended trough level [Table 4]. We also observed an inter-individual and intra-individual variation of trough levels.
Thus far, very few articles have been published regarding conversion to everolimus and CNIs withdrawal protocol in CAN. Our study showed that in CAN, conversion to everolimus with complete withdrawal of CNIs is safe and simple when recipient's cGFR is more than 30 mL/min.
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Department of Nephrology, Nizam's Institute of Medical Sciences, Punjagutta, Hyderabad 500082, Andhra Pradesh
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]