EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: The mammalian target of rapamycin inhibitors sirolimus and everolimus are immuno-suppressive drugs for kidney transplant patients, but adverse events may include proteinuria. The purpose of this study was to compare the effects of sirolimus and everolimus on creatinine clearance and proteinuria after kidney transplant.

Materials and Methods: This study was a prospective evaluation period of 50 patients (age, 16-65 y) who had kidney transplant. There were 25 patients who used sirolimus and 25 patients who used everolimus. Evaluation at the beginning mTOR and end of the evaluation period included complete blood count, blood pressure, serum creatinine level, creatinine clearance, and proteinuria level in a 24-hour urine collection.

Results: Mean creatinine clearance at the beginning and end of the evaluation period was significantly less in the everolimus than sirolimus group. There was no significant change in creatinine clearance from the beginning to end of the evaluation period in either the sirolimus or everolimus group. Mean proteinuria at the beginning and end of the evaluation period was similar between the sirolimus and everolimus groups. Both groups had a significant increase in mean proteinuria from beginning to end of the evaluation period, but the increase in proteinuria was similar for the sirolimus and everolimus groups (difference not significant).

Conclusions: In kidney transplant recipients, sirolimus and everolimus are associated with a similar level of increased mean proteinuria.

Key words : End-stage kidney disease, Everolimus, Immunosuppression, Sirolimus

Mammalian target of rapamycin (mTOR) inhibitors are potent immunosuppressive drugs that commonly are used in patients who have heart and kidney transplant. The mTOR inhibitors include sirolimus (a macrocyclic lactone antibiotic produced by Streptomyces hygroscopics) and everolimus (a derivative of sirolimus). By modulating mTOR activity, these drugs inhibit the response of cells to interleukin 2, prevent DNA and protein synthesis, and cause arrest of the cell cycle.^1,2 In contrast with calcineurin inhibitors, the mTOR inhibitors may not have nephrotoxic adverse events. The mTOR inhibitors also may have beneficial effects such as antitumor activity.³

The primary disadvantage of mTOR inhibitors is increased proteinuria, and this may limit the use of these drugs in kidney transplant patients.^4,5 Proteinuria may occur in patients who are on maintenance immunosuppression and who are converted to mTOR inhibitors or patients who have pre-existing proteinuria, but not patients with de novo mTOR inhibitor use.^6-8 Therefore, conversion to everolimus is not advised in patients who have pre-existing proteinuria > 800 mg/day.⁹ Proteinuria is inversely associated with survival in transplant patients.

The clinical use of sirolimus began in 1997 and everolimus in 2004, and there are more clinical studies about the adverse events with sirolimus than everolimus. Although the drugs have similar molecular structure and may have similar adverse events, few studies have compared adverse events with these 2 drugs. The purpose of this study was to compare the effects of sirolimus and everolimus on creatinine clearance and proteinuria after kidney transplant.

Materials and Methods

Subjects
This study was a prospective evaluation of 50 patients (age, 16-65 y) who had kidney transplant and were followed at Haydarpaşa Research and Training Hospital Transplantation Center. Sequential patients were selected randomly for the study. There were 25 patients who used sirolimus and 25 patients who used everolimus. Exclusion criteria included cirrhosis and metastatic cancer. There were 28 patients (sirolimus group, 13 patients; everolimus group, 15 patients) who were changed to them TOR inhibitor, and the other patients had the mTOR inhibitor as part of the initial therapy after transplant. All patients received another immunosuppressive drug (mycophenolate mofetil, 46 patients; azathioprine, 2 patients; cyclosporine, 2 patients) and corticosteroids. Dosage of the mTOR inhibitor was adjusted to achieve target serum levels (sirolimus, 4-12 ng/mL; everolimus 3-8 ng/mL). Evaluation at the beginning mTOR treatment and end of the evaluation period included a complete blood count, blood pressure, serum creatinine level, creatinine clearance, and proteinuria level in a 24-hour urine collection. The study was approved by the Ethical Review Committee of the institute, and all protocols conformed with the ethical guidelines of the 1975 Helsinki Declaration. Informed written consent was obtained from all subjects.

Statistical analyses
Statistical analyses were performed with SPSS software (SPSS: An IBM Company, version 13.0, IBM Corporation, Armonk, NY, USA). Results were expressed as mean ± SD. Serum creatinine and proteinuria levels at the beginning and end of the evaluation period were compared using Wilcoxon
1-way analysis of variance. The groups were compared with post hoc least significant difference test and Pearson product moment correlation. All statistical tests were 2-sided. Statistical significance was defined by P ≤ .05.

The most frequent causes of kidney disease were chronic pyelonephritis, hypertension, diabetic nephropathy, and unknown causes (Table 1). In the sirolimus group, 13 patients were changed from a calcineurin inhibitor because of chronic allograft nephropathy and/or calcineurin toxicity (11 patients), suspicion of malignancy (1 patient), or BK virus infection (1 patient). In the everolimus group, 15 patients were changed from a calcineurin inhibitor because of chronic allograft nephropathy and/or calcineurin toxicity (8 patients), suspicion or presence of malignancy (4 patients), adverse events with calcineurin inhibitors (2 patients), or BK virus infection (1 patient).

In all patients combined, mean creatinine level was similar between the beginning of the evaluation period (146 ± 59 μmol/L) and end of evaluation period (156 ± 61 μmol/L); (not significant), and the difference between groups was not significant (Table 2). There was no significant change in creatinine level from the beginning to end of the evaluation period in either the sirolimus or the everolimus group (Table 2).

Mean creatinine clearance at the beginning and end of the evaluation period was significantly less in the everolimus than in the sirolimus group (Table 2). There was no significant change in creatinine clearance from the beginning to end of the evaluation period in either the sirolimus or everolimus group (Table 2).

Mean proteinuria at the beginning or end of the evaluation period was similar between the sirolimus and the everolimus groups (Table 2). Both groups had a significant increase in mean proteinuria from beginning to end of the evaluation period (Table 2), but the increase in proteinuria was similar for the sirolimus and everolimus groups (difference not significant). The number of patients who had proteinuria had increased from the beginning to end of evaluation period for both sirolimus group (> 0.3 g/d: beginning, 10 patients [40%]; end, 12 patients [48%]) (> 1 g/d: beginning, 2 patients [8%]; end, 3 patients [12%]) and everolimus group (> 0.3 g/d: beginning, 13 patients [52%] patients; end, 16 patients [64%]) (> 1 g/d: beginning, patients [12%]; end, 4 patients [16%]). Patients who had initial proteinuria > 1 g/day were changed from a calcineurin inhibitor to mTOR inhibitors because of malignancy and BK virus infection. There was 1 patient in the sirolimus group who developed nephrotic range proteinuria from beginning to end of evaluation period.

Adverse events that may occur with calcineurin inhibitors include negative effects on blood pressure control and nephrotoxicity. By inhibiting mTOR, the mTOR inhibitors have pleiotropic effects that cause effective immunosuppression and may help improve long-term outcomes. The mTOR inhibitors may inhibit the development of chronic allograft nephropathy/interstitial fibrosis and tubular atrophy, cytomegalovirus, BK virus infection, and malignancy. However, treatment with mTOR inhibitors may be complicated by nephrotic syndrome and proteinuria, which are important indicators of graft loss.

There are several trials that showed that sirolimus may be associated with proteinuria.^4,10,11 Everolimus also may cause proteinuria.^5,11,12 The present results were similar to previously reported data and showed that both sirolimus and everolimus may cause proteinuria (Table 2). The increase in proteinuria was more severe in patients who had pre-existing proteinuria. Both groups had an increase in mean proteinuria, but the difference in the increase between the groups was not significant. Other adverse events with mTOR inhibitors including anemia, hyper-lipidemia, and frequent infections were observed as described previously (data not shown).

The initial mean creatinine clearance level was lower for the everolimus than the sirolimus group (Table 2), possibly because of selection bias by the specialists who prescribed the drugs to the patients. Further evaluation of this issue may include a randomized trial.

The purpose of this trial was to compare levels of proteinuria between patients who received sirolimus or everolimus. There was no significant difference in the increase in mean proteinuria between the sirolimus and everolimus groups. The mean creatinine levels and creatinine clearance were stable in both sirolimus and everolimus groups (Table 2).

Limitations of the present study included the limited number of patients that precluded subgroup evaluation for proteinuria and creatinine clearance levels. Further study with more patients is justified to evaluate the effects of secondary immunosuppressive drugs and differences between patients who had mTOR inhibitors de novo or who were changed to mTOR inhibitors from other immunosuppressive drugs.

The mTOR inhibitors are promising immuno-suppressive drugs, especially for patients who have adverse events with calcineurin inhibitors, malignancy, or older donors. Proteinuria is a potential limiting factor for the use of mTOR inhibitors. Although sirolimus and everolimus are associated with the development of de novo or increased proteinuria, the present study showed only 1 patient who developed nephrotic range proteinuria with these drugs. The present study showed that the increase in mean proteinuria was similar between sirolimus and everolimus.

Volume: 12 Issue: 6 December 2014

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