Long-term allograft survival after kidney transplantation faces two important obstacles: chronic allograft nephropathy (CAN) and death with a functioning kidney. The pathogenesis of CAN has been extensively studied in recent years, although no therapeutic options are available to treat it. This could be due to the multifactorial process leading to late allograft dysfunction. Both immunological and nonimmunological factors contribute to this process, and calcineurin inhibitor (CNI) toxicity has been identified as an important nonimmunological factor (1, 2). Indeed, although CNIs have substantially decreased the risk of acute rejection and improved short-term outcomes in kidney recipients, it must be highlighted that these drugs also contribute to renal fibrosis and long-term graft loss (1–4). Moreover, CNIs could increase cardiovascular risk and the development of tumors (3, 4) and, consequently, favor death with a functioning graft.
Therefore, management of kidney recipients after the first period of high immunological risk involves minimization of immunosuppression and management of CAN. Minimization strategies aim to reduce the unwanted side effects of immunosuppressive agents while preserving graft function and decreasing the risk of rejection. Such approaches include minimization of CNI doses or withdrawal to and conversion to mammalian target of rapamycin (mTOR) inhibitors. These drugs have three potential beneficial effects, namely, a relative lack of nephrotoxicity, antineoplastic (5), and antiatherosclerotic properties (6). Some authors have provided information of conversion from a CNI to sirolimus (SRL) in maintenance kidney transplant patients (7). A meta-analysis (8) examining conversion to SRL in patients with chronic graft dysfunction demonstrated improved short-term renal function but high withdrawal rates because of adverse effects (28%). Another exhaustive review (9) in patients with progressive renal dysfunction converting from CNIs to SRL demonstrated that conversion was safe (because of the low rejection rates reported) and may lead to improved renal function if initiated early. Further studies with SRL show similar results (10–15).
Little is known about the use of everolimus (EVL) in this field. A few clinical studies with small samples have been published in patients with CAN or CNI toxicity (16–19). In most cases, CNIs were suspended, and the results showed a tendency toward improved renal function (16–18).
The aim of this study was to describe our clinical experience with EVL and to determine prognostic factors for successful conversion in a large and uniform cohort of kidney recipients.
The mean age at conversion was 55.9±13.2 years, and the median time from transplant to conversion was 69.4 months (interquartile range [IQR] 13.7–129.9 months), with a range between 3 and 291 months posttransplant. Sixty-seven percent of patients were men, and 88.6% of cases were first transplants. Fifty-five percent of patients were under tacrolimus treatment and 45% under cyclosporine treatment. Seventy-seven percent of patients received mycophenolate and 7.7% azathioprine. A total of 43.2% of the patients were treated with prednisone (see Table, SDC 2,http://links.lww.com/TP/A580).
EVL was introduced at an initial dose of 2.95±0.69 mg/day, and the first level at the fourth day was 8.91±5.22 ng/mL.
Indications for Conversion
The main indication for conversion was tumor in 80 cases (36%). The most frequent indication in this subgroup was recurrent basal and/or squamous cutaneous carcinoma (42 cases). Other tumors were renal carcinoma (n=9), digestive tract neoplasm (n=6), posttransplant lymphoma (n=4), prostate cancer (n=4), Kaposi sarcoma (n=3), malignant melanoma (n=3), and others (n=9).
The second cause was interstitial fibrosis and tubular atrophy (68 cases, 30.6%). The third reason for conversion was severe generalized vascular disease (28 cases, 12.6%). Despite having a normal renal function, 22 patients (11.7%) were converted as a preventive strategy in the first year after transplant. CNI was switched to EVL in six patients because of neurotoxicity (2.7%), in four patients because of acute nephrotoxicity (1.8%), and in eight patients for other reasons (3.6%).
Acute Rejection Episodes After Conversion
After conversion, nine patients (4.1%) developed biopsy-proven acute rejection. All were Banff type I (n=8) or II (n=1) and corticosteroid sensitive. None of the patients lost their graft as a consequence of acute rejection.
Discontinuation of EVL
Treatment with EVL was stopped due to adverse events in 77 patients (34.7%). Mean suspension time was 6.2 months (IQR 1.6–16.6 months), with most suspensions occurring during the first year after initiation (53 patients; see Figure, SDC 3,http://links.lww.com/TP/A581). The main reasons were pneumonitis (n=17, 7.7%), proteinuria (n=9, 4.1%), acute rejection (n=8, 3.6%), renal function impairment (n=6, 2.7%), severe skin eruption (n=6, 2.7%), and infection (n=5, 2.3%).
Outcome After Conversion
We followed 197 patients for at least 1 year (in the remaining 23 patients, the time of follow-up was <12 months). Baseline creatinine clearance (CrCl) was 52.4±17.8 mL/min compared with 53.4±20.1 mL/min at 1 year (P=0.150) in the intention-to-treat group. These patients experienced progressive impairment in renal function (CrCl 3 months before conversion, 53.2±17.9; P=0.016 compared with baseline). In the analysis of the patients in whom EVL was maintained (on-treatment group, n=158), CrCl 3 months before conversion was 53.9±18.4 mL/min compared with 52.7±17.1 mL/min at baseline (P=0.009 compared with 3 months before conversion) and 54.9±19.0 mL/min at 1 year after conversion (P<0.001 compared with baseline). In patients in whom EVL was stopped in the first year (n=39), there was a deterioration in renal function although without statistical significance (50.0±19.2 [baseline] vs. 46.8±22.9 mL/min [1 year]; P=0.092).
Renal function was stratified in baseline CrCL and proteinuria. A statistically significant improvement was observed in patients who were converted with a baseline CrCl ≥40 mL/min and baseline proteinuria <550 mg/day (P=0.005).
The evolution of renal function and proteinuria stratified by cause of conversion is listed in Table 1.
In the 197 patients who completed the first year of follow-up, baseline proteinuria was 304 mg/day (IQR, 160–507), increasing to 458 mg/day (IQR, 238–892; P<0.001) 1 year after conversion in the intention-to-treat group and to 423 mg/day (IQR, 223–780; P<0.001) in the on-treatment group. Proteinuria levels increased in the overall group independently of the cause of conversion (Table 1). However, before conversion, there was not a significant increase in proteinuria (proteinuria 3 months before conversion, 274 mg/day, IQR 133–598; P=0.588 compared with baseline).
Baseline proteinuria in the control group was lower than in the EVL group (201 mg/day, IQR 117–360; P=0.001 vs. EVL group). At 1 year, proteinuria levels remained unchanged (186 mg/day, IQR 120–395; P=0.208 vs. baseline).
Impact of Baseline Parameters on Proteinuria After Therapy With EVL
The univariate analysis of the baseline parameters for developing proteinuria ≥900 mg/day (P75) 1 year after conversion is listed in Table 2.
A logistic regression model was constructed to evaluate independent prognostic factors for risk of proteinuria ≥900 mg/day 1 year after conversion (Table 2, first model). To study the impact of EVL in proteinuria, we excluded 19 patients who had stopped EVL in the first 3 months or who presented acute rejection after conversion. The independent prognostic factors were age, CrCl <60 mL/min, serum triglycerides ≥150 mg/day, and no treatment with prednisone. Data also show that patients with baseline proteinuria more than 550 had a 10.37-fold greater risk of developing proteinuria after 1 year. Patients who were converted ≥3 years after transplant had also high risk. The sensitivity of the model was 82% and the specificity was 81%, with an area under the curve of 0.86 (95% confidence interval [CI]: 0.79–0.92; P<0.001).
We then evaluated whether prognosis varied according to time of conversion and baseline proteinuria. Time of conversion was clinically relevant for obtaining a good prognosis (P for the interaction, 0.02; Table 2, interaction model). In patients with baseline proteinuria less than 550 mg/day, time of conversion was not associated with a poor outcome (adjusted risk 16.21% for ≥3 years vs. 11.10% for <3 years). However, in patients with baseline proteinuria ≥550 mg/day, time of conversion was associated with a poor outcome (77.07% for ≥3 years vs. 29.81% for <3 years).
There were no differences at any time between EVL levels in patients with proteinuria less than 900 mg/day and proteinuria ≥900 mg/day 1 year after EVL conversion (Table 3; see SDC 4,http://links.lww.com/TP/A582).
Impact of Baseline Parameters on Renal Function at 1 Year
Figure 1 shows the percentage of patients who experienced a ≥8% loss in CrCl during the year of follow-up stratified by time of transplant after conversion and baseline proteinuria.
In patients who were converted during the first 3 years, baseline proteinuria ≥550 mg/day did not affect loss of renal function (16.3 vs. 15.4% of patients lost >8% of CrCL; P>0.999). However, this loss of glomerular filtrate affected 46.4% of patients who were converted after 3 years with high baseline proteinuria compared with 19.3% whose proteinuria was below that figure (P=0.007).
Patient and Graft Survival After Conversion
Actuarial graft survival at 1 and 4 years postconversion was 98.2% and 86.5%, respectively. Figure 2 shows graft survival (death censored) stratified by time of conversion after transplant and baseline proteinuria. We observed no differences in graft survival in patients converted before 3 years when they were stratified by baseline proteinuria (Fig. 2A; P=0.351). However, in patients converted after 3 years (Fig. 2B), proteinuria ≥550 mg/day indicated a poor prognosis for graft survival (P<0.001).
Patient survival was 98.6% and 92.1% at 1 and 4 years, respectively. During the median time of 4 years of follow-up, six patients died due to cardiovascular disease, four due to previous cancer, one due to infection, and one of unknown causes.
A CNI-based regimen is the cornerstone of immunosuppressive therapy after kidney transplantation. CNIs have reduced acute rejection and infection rates and markedly increased short-term kidney graft survival (20). However, the nephrotoxic effect of CNI can limit long-term graft survival (20). Most recent strategies to avoid exposure to CNI have focused on immunosuppressive drugs that are generally considered non-nephrotoxic, such as the mTOR inhibitors. EVL is a novel rapamycin analog proliferation signal inhibitor with potent immunosuppressive activity. It has demonstrated potent antiproliferative effects and has prevented allograft rejection in preclinical models (21, 22). EVL was also found to be safe and efficacious in phase III multicenter studies in de novo heart or kidney transplant patients (23–26).
The few published clinical studies on conversion to EVL in maintenance transplants have small sample sizes (16–18). We report the largest series to date. Before conversion, our series showed a statistically significant trend toward progressive impairment of renal function. However, 1 year after conversion, renal function stabilized. It is important to remember that the main objective of conversion in patients with deteriorating renal function is stabilization, more than a significant improvement in renal function in a kidney with established chronic irreversible lesions. This is especially important if we consider that renal function at conversion was considerably better in our series than in others, such as that of Diekmann et al. (27), who reported an improvement in renal function in a series of patients converted to SRL; however, mean serum creatinine at conversion in this series was 3.1 mg/dL, whereas in ours it was 1.7 mg/dL. The principal benefit in our series was obtained in patients who were converted with CrCl more than 40 mL/min and low baseline proteinuria, as shown by the CONVERT trial (largest series of patients converted to SRL) (7). The negative effect of EVL conversion in our study was an increase of proteinuria levels at 1 year postconversion. This effect on proteinuria is one of the main challenges in mTOR conversion and its long-term consequences must be determined. When we studied the control group, although basal proteinuria was low, no increment on proteinuria was found.
In experimental models, EVL was shown to ameliorate progression of CAN, not only when administered prophylactically from the time of transplantation (28) but also in advanced disease (29). The mechanism of action of EVL in CAN includes blocking growth factor-induced proliferation of immune cells and nonimmune cells such as vascular smooth muscle cells, tubular epithelial cells, and fibroblasts (30–32). Data suggest that EVL could prevent allograft vasculopathy (reviewed in ).
Our data on EVL are consistent with those published on SRL. A meta-analysis of studies examining conversion from CNIs to SRL in patients with chronic graft dysfunction (8) revealed improved long-term renal function; however, it also revealed a high rate of dropouts due to adverse events (28%). Another exhaustive review (9) of articles on patients with progressive impairment of renal function who converted from CNIs to SRL showed that the switch was safe because of the low rejection rate reported and that it could lead to an improvement in renal function if made early, that is, before structural damage was advanced. Between 20% and 46% of patients did not respond to the conversion. Subsequent studies on SRL show similar results (10, 12–15). Our dropout rate in the first year was 24%.
Consistent with the results of previous reports, we found that some patients developed a significant increase in proteinuria when switched to mTOR inhibitors (7, 8, 27, 34–46). In our study, almost 25% of the patients treated with EVL developed proteinuria ≥900 mg/day 1 year after conversion. The factors associated with the development of proteinuria after conversion to EVL were time to conversion after transplantation, level of baseline proteinuria and renal function, age, hypertriglyceridemia, and lack of treatment with prednisone. We also observed an interaction between baseline proteinuria and time after conversion: in patients who were converted before the third year after transplant, high baseline proteinuria was not associated with a greater risk of developing severe proteinuria 1 year after transplant, whereas it is an indicator of poor prognosis if conversion is made later. Proteinuria more than 550 mg/day in patients who were converted after the third year after transplant could well be a marker of glomerular damage and, therefore, imply a high risk of deterioration; however, during the first years after transplant, proteinuria more than 550 mg/day could point to other diseases.
The rate of proteinuria is reported to be lower if angiotensin convertine enzyme inhibitors or angiotensin receptor blockers are used in SRL-treated patients (47). In our study, 64% of patients were treated with these drugs before conversion and 71% at 1 year postconversion. It is not possible to study the impact of these drugs on the development of proteinuria, because they are used in all patients who have proteinuria and tolerate these drugs. One study with 48 patients treated with SRL has suggested that statins had a protective effect on the development of proteinuria, although our results do not confirm these data (44). Nevertheless, we did observe hypertriglyceridemia to be a risk factor for proteinuria.
Our study showed that factors that were negative for graft survival and loss of renal function 1 year after conversion were different depending on the timepoint at which the conversion was made. In patients who converted to EVL ≥3 years after transplant, proteinuria more than 500 mg/day predicted a poor response; however, baseline proteinuria did not predict poor outcome if the conversion was before 3 years. Diekmann et al. (27) used SRL in 59 kidney recipients with CAN. They found that proteinuria less than 800 mg/day had a positive predictive value of 90% for a positive response to SRL. The extended follow-up of the cohort confirmed this finding (14). Nevertheless, our data shed more light on these findings, because the time after transplant when CNIs are converted to EVL seems to play an important role in prognosis. Furthermore, we defined a lower proteinuria cutoff (550 mg/day, corresponding to P75 of our sample) as a risk factor. Our greater sample size could explain our novel findings.
The main limitation of our study is the lack of a control group because of the characteristics of our patients (tumors, chronic dysfunction, etc.), for this reason this limitation is difficult to overcome.
To conclude, CNI elimination with conversion to EVL is a safe procedure with respect to the risk of acute rejection and it can slow progression in those patients with deteriorating renal function. The rate of dropouts due to adverse events is similar to that reported in other publications. Some are predictable, such as increased proteinuria. Early or intermediate conversion might be associated with a higher success rate even in patients with high baseline proteinuria.
MATERIALS AND METHODS
From March 2005 to January 2010, a total of 220 renal transplant patients were converted to EVL as their primary immunosuppressive agent in two hospitals, one in Madrid (Hospital Clínico San Carlos, 131 patients) and the other in Santander (Hospital Universitario Marqués de Valdecilla, 91 patients). The median follow-up was 45 months (IQR 29–55 months).
To evaluate the effect of EVL on proteinuria development, we analyzed a control group that included all functioning renal transplants performed with the contralateral organs from the same donors. A total of 145 patients were recorded. Baseline CrCl was similar to that of the study group (53.9±14.5 mL/min; P=0.367).
Conversion From a CNI-Based Protocol to an EVL-Based Protocol
On the day EVL was started, doses of the CNI were reduced by 50%. The level of EVL was measured on day 4 after initiation; when it was in the desired range (≥3 ng/mL), the CNI was completely eliminated.
All the patients were evaluated 4 and 8 days after conversion to adjust blood levels and at days 30, 60, 90, and every 3 months thereafter to adjust blood levels, detect adverse events, and evaluate graft outcome. At each visit, the variables recorded were renal function (serum creatinine and glomerular filtration rate estimated using the Cockcroft-Gault formula), 24-hour urine protein excretion, blood count, cholesterol, and triglycerides. The presence of clinically detectable adverse events was actively investigated. All the patients were followed until the end of the study period (December 2010) for graft and patient survival analysis.
The variables used to evaluate outcome after conversion were presence of proteinuria ≥900 mg/day at 1 year after conversion (representing the 75th percentile), loss of renal function more than 8% of glomerular filtration rate at 1 year (representing the 25th percentile), graft loss, and patient death.
Continuous variables (expressed as means±standard deviation) were compared using the t test; categorical variables were compared using the chi-square test or Fisher's exact test. Asymmetric variables were expressed as the median (IQR) and were compared using the Kruskal-Wallis test.
A multivariate logistic regression analysis was conducted to identify predictive factors for the development of proteinuria ≥900 mg/day at 1 year after conversion and for the deterioration of renal function. Clinical parameters were compared between groups (patient demographics, comorbidities, immunosuppression, concomitant medication, and laboratory parameters such as baseline proteinuria and CrCl).
The analysis strategy was univariate (incidence) followed by a stratified analysis (to explore interactions). Adjusted odds ratios and their 95% CI were calculated using estimated regression coefficients and their standard errors in the logistic regression analysis. The existence of interactions was evaluated. Clinically relevant variables and those showing a P value less than 0.10 in the univariate analysis were selected for the multivariate analyses. The Kaplan-Meier method and the Breslow exact test were used to evaluate differences in graft survival. The null hypothesis was rejected in each statistical test when P was less than 0.05. The statistical analysis was performed using SPSS for Windows, version 15.0.
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