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Early Steroid Withdrawal and Optimization of Mycophenolic Acid Exposure in Kidney Transplant Recipients Receiving Mycophenolate Mofetil

Le Meur, Yannick1,20; Thierry, Antoine2; Glowacki, François3; Rerolle, Jean-Philippe4; Garrigue, Valerie5; Ouali, Nacera6; Heng, Anne-Elisabeth7; Delahousse, Michel8; Albano, Laeticia9; Lang, Philippe10; Couzi, Lionel11; Jaureguy, Maite12; Lebranchu, Yvon13; Mousson, Christiane14; Glotz, Denis15; Kessler, Michele16; Vrtovsnik, François17; Rouanet, Stephanie18; Tagieva, Nailya18; Kamar, Nassim19

doi: 10.1097/TP.0b013e318234e134
Clinical and Translational Research
Free
SDC

Background. Early posttransplant steroid withdrawal may increase the risk of acute rejection and the occurrence of subclinical acute rejection (SCAR). We assessed the feasibility and safety of early steroid withdrawal in low-risk patients receiving cyclosporine A (CsA) and the impact of optimization of mycophenolic acid exposure on steroid withdrawal success.

Methods. De novo, low-immunological risk kidney recipients received an anti-interleukin-2-receptor-α antibody induction, a short course of 7 days of corticosteroids, and CsA with 2-hr postdose concentration monitoring. They were randomized to adjusted dose (AD) of mycophenolate mofetil (MMF) using therapeutic drug monitoring (TDM) or a fixed-dose (FD) regimen. MMF 3 g was initiated posttransplant and then adjusted starting at week 2 to a 0 to 12 hr area under the concentration time curve of 40 mg · h/L versus 2 g daily, respectively. The primary endpoint was a composite of the proportion of patients experiencing biopsy-proven acute rejection (BPAR) and those with SCAR identified on the 3-month protocol biopsy.

Results. Among 247 analyzed patients, only 22 in the AD group and 17 in the FD group experienced BPAR or SCAR (P=0.46). The rate of SCAR was low: 4% (AD) and 2.5% (FD). No between-group difference in the incidence of BPAR was observed. TDM yielded MMF doses ranging from 1 to 4 g/d and significantly reduced interpatient variability at weeks 26 and 52 in the AD group.

Conclusions. In low-immunological risk kidney recipients, MMF combined with CsA allows early corticosteroid discontinuation with good tolerability. In this group of patients, TDM of MMF does not improve clinical outcome.

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1 Department of Nephrology, University Hospital, Brest, France.

2 Department of Nephrology, University Hospital, Poitiers, France.

3 Department of Nephrology, University Hospital, Lille, France.

4 Department of Nephrology and Transplantation, Limoges, France.

5 Department of Nephrology, Transplantation and Peritoneal Dialysis, University Hospital, Montpellier, France.

6 Department of Nephrology and Transplantation, Tenon Hospital, Paris, France.

7 Department of Nephrology, University Hospital, Clermont-Ferrand, France.

8 Department of Nephrology and Transplantation, Foch Hospital, Suresnes, France.

9 Department of Nephrology and Transplantation, University Hospital, Nice, France.

10 Department of Nephrology and Transplantation, Henri Mondor Hospital, Paris, France.

11 Department of Nephrology, Transplantation and Dialysis, Bordeaux, France.

12 Department of Nephrology, University Hospital, Amiens, France.

13 Department of Nephrology and Clinical Immunology, University Hospital, Tours, France.

14 Department of Nephrology, University Hospital, Dijon, France.

15 Department of Nephrology and Transplantation, Saint-Louis Hospital, Paris, France.

16 Department of Nephrology and Dialysis, University Hospital, Nancy, France.

17 Department of Nephrology, Bichat Hospital, Paris, France.

18 Roche SAS, Neuilly-sur-Seine, France.

19 Department of Nephrology, Dialysis and Organ Transplantation, University Hospital, Toulouse, France.

This work was supported by Roche SAS, France.

The following authors declare these conflicts of interest: Profs. Le Meur, Kamar, Lebranchu, and Glotz have received consulting fees and grant support from Roche SAS. S. Rouanet and Dr. Tagieva are employees of the study sponsor. The following authors of this manuscript declare no conflicts of interest: Drs. Thierry, Glowacki, Rerolle, Garrigue, Ouali, Heng, Delahousse, Albano, Couzi, Jaureguy, and Profs Lang, Mousson, Kessler and Vrtovsnik.

20 Address correspondence to: Yannick Le Meur, M.D., Ph.D., Department of Nephrology, University Hospital La Cavale Blanche, Rue Tanguy Prigent, 29609 Brest Cedex, France.

E-mail: yannick.lemeur@chu-brest.fr

Y.L.M., S.R., N.T., and N.K. participated in research design. Y.L.M., J.-P.R., A.-E.H., S.R., N.T., and N.K. participated in data analysis, in writing of the manuscript, or critically reviewed the content. All authors participated in performance of the research and approved the final manuscript for publication.

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal's Web site (www.transplantjournal.com).

Received 16 May 2011. Revision requested 6 June 2011.

Accepted 26 August 2011.

Steroid minimization is one of the most important preoccupations in transplantation. Not only are steroids responsible for serious adverse events, such as Cushing's syndrome, osteoporosis, myopathy, or increased susceptibility to infection, but also more importantly they contribute to the high cardiovascular risk profile of the graft recipients by worsening hypertension, hyperlipidemia, and glucose intolerance and are associated with increased cardiovascular morbidity (1). Historically, late steroid withdrawal (after 6 months) has been associated with increased acute rejection rates and graft loss (2). More recently, two systematic reviews concluded that steroid withdrawal has no impact on patient or graft survival although this strategy increases the risk of acute rejection (3, 4). However, with the potent induction and maintenance immunosuppressive agents now available, early steroid withdrawal (<7 days of steroids) has been successful primarily in patients receiving tacrolimus (5–7). Still, early steroid withdrawal also may increase the risk of acute rejection particularly for patients under cyclosporine A (CsA) (8, 9). Furthermore, early protocol biopsies have revealed the presence of subclinical acute rejection (SCAR) and borderline changes, major risk factors for the development of chronic allograft nephropathy (10).

A strong correlation exists between mycophenolic acid (MPA) exposure and renal transplant outcomes (11). Mycophenolate mofetil (MMF) dose adjustment based on MPA exposure can reduce the incidence of acute rejection in CsA-treated graft recipients (12). The objective of this study was to assess the feasibility and safety of early steroid withdrawal in low-risk patients receiving CsA and the impact of optimization of MPA exposure on steroid withdrawal success.

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RESULTS

Patient Disposition and Demographic Characteristics

The study was conducted between May 2006 and July 2008. Among the 258 randomized patients (adjusted-dose [AD] group, n=130; fixed-dose [FD] group, n=128), five patients did not receive MMF and one patient did not sign the consent form. As a result, 252 patients were included in the safety population, and, among them, 247 patients were analyzed in the intention-to-treat population (five patients received the first dose of MMF but did not undergo transplantation) (Fig. 1). Study groups were well balanced with respect to baseline characteristics (Table 1); all patients were considered at low immunological risk. A statistically significant difference was observed between treatment groups in donor-recipient cytomegalovirus (CMV) serology status (P=0.004), resulting from a higher D+/R− status (30.2% in the AD group vs. 14.1% in the FD group). Kidney grafts mostly came from deceased donors (96%).

FIGURE 1.

FIGURE 1.

TABLE 1

TABLE 1

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Immunosuppressant Dose and Exposure

Patients in the AD group received MMF 3 g/d for the first 10 days posttransplant. Significantly higher MPA exposure was observed in this group at week 2 compared with the FD group receiving 2 g/d (MPA area under the concentration-time curve [AUC0–12]: 36.2±14.8 mg · h/L vs. 29.3±12.4 mg · h/L, respectively; P<0.001). After day 10, the MMF dose was adjusted to achieve the MPA AUC0–12 target of 40 mg · h/L and MPA exposure remained higher at week 6 (AD, 44.2±16.1 mg · h/L vs. FD, 36.8±18.1 mg · h/L; P=0.002) (Fig. 2A). Consequently, more patients in the AD group achieved therapeutic concentrations: 66% vs. 38% at week 2 and 81% vs. 62% at week 6 had an MPA AUC0–12 more than 30 mg · h/L, the lower limit of the recommended therapeutic window (Fig. 2B). According to the dose adjustment recommendations, patients in the AD group were to receive a mean dose of 3 g/d of MMF for the first 3 months and some patients needed as much as 4 g/d (Fig. 3A), whereas in the FD group, mean doses progressed downward beginning at week 6 (Fig. 3B). At weeks 12 and 16, the mean daily doses in the AD group decreased to 2.5±0.9 g and 2.2±0.9 g, respectively, and then were approximately 2 g at the following visits (week 26: 2.0±0.9 g; weeks 39 and 52: 1.9±0.8 g) (Fig. 3C). An analysis of distributions showed a higher AUC variability at weeks 26 and 52 in the FD group versus the AD group, confirmed by a Folded F test for equality of variances (week 26: SD=15.0 in the AD group; SD=20.4 in the FD group; P=0.005; week 52: SD=14.9 in the AD group; SD=21.8 in the FD group; P<0.001). CsA C2 levels were similar between groups and were consistent with the predefined target levels, mean C2 levels at week 2, 12, 26, and 52 in AD and FD group, respectively: 1187±409 vs. 1233±373, 1142±398 vs. 1246±415, 927±194 vs. 896±318, 658±409 vs. 721±253 (see Figure, SDC 1, http://links.lww.com/TP/A561).

FIGURE 2.

FIGURE 2.

FIGURE 3.

FIGURE 3.

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Efficacy

The composite primary endpoint was similar between treatment groups: 22 of 126 (17.5%) in the AD group vs. 17 of 121 (14.1%) in the FD group (P=0.46). There was no difference between the two groups in terms of the proportion of patients with biopsy-proven acute rejection (BPAR) at 3 months or SCAR as determined by protocol biopsy at month 3 (Table 2). These findings were confirmed at 1 year with a similar rate of BPAR (24.6% in the AD group vs. 14.9% in the FD group; P=0.06) and of SCAR (9.3% in the AD group vs. 10% in the FD group; P=0.84) between treatment groups. At 1 year, a similar proportion of protocol biopsies presented as chronic lesions (interstitial fibrosis and tubular atrophy ≥1: 47.5% in the AD group vs. 52.5% in the FD group; P=0.72), and renal function was also similar (mean estimated creatinine clearance: 50.8±16.3 mL/min/1.73 m2 in the AD group and 48.9±18.2 mL/min/1.73 m2 in the FD group). Patient and graft 1-year survival rates were excellent in both groups: 98% and 95%, respectively; six grafts were lost in each group, with the majority due to early thrombosis.

TABLE 2

TABLE 2

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Safety

The overall incidence of adverse events was similar for the two treatment regimens. In particular, there was no difference in the incidence or severity of CMV, herpes, or bacterial infections. Furthermore, the incidence of diarrhea, anemia, or leukopenia was not different between patients in the AD and FD groups (Table 3). The percentage of patients who had MMF dose adaptation due to an adverse event was significantly greater in the AD than in the FD group (58.7% vs. 42.2%, respectively; P=0.009). However, the number of patients who discontinued MMF between baseline and week 52 was similar between groups (11.1% in the AD group; 12.4% in the FD group; P=0.754).

TABLE 3

TABLE 3

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Steroid Withdrawal

Steroid withdrawal was possible at day 7 in 94% of patients in both groups. At 1 year, 67% of patients in the AD group and 69% in the FD group were still free of steroids. Apart from suspected rejections (biopsy proven or not), the main reason for reintroduction of steroids in both groups was borderline lesion treatment: at the end of the study, 21 patients had been treated in AD group versus 28 in the FD group. The incidence of adverse events associated with corticosteroids as de novo diabetes mellitus was low. One-year blood pressure was identical in the two groups: 137/79 mm Hg vs. 137/78 mm Hg.

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DISCUSSION

We conducted this randomized, multicenter trial to assess the benefit of the combination of early corticosteroid withdrawal with intensified MMF dosing and therapeutic drug monitoring (TDM) in kidney transplant recipients receiving CsA maintenance immunosuppression. Two recent systematic reviews confirmed that early steroid withdrawal strategies increase the risk of acute rejection (3, 4) Our results indicate that early steroid withdrawal (<7 days) is feasible and safe in selected patients with a 70% success at 1 year. In fact, only 39 patients in both groups (15.8%) experienced BPAR or SCAR at 3 months posttransplant. Compared with previous published studies (13, 14), this is the first trial that has shown a low acute rejection rate after early steroid withdrawal in low-risk patients receiving anti-interleukin-2-receptor-α (IL-2Rα) induction, CsA, and MMF. In the Freedom study, with a similar immunosuppressive regimen, the 3 months rate of BPAR was 18.3%, but SCAR were not analyzed (14). Per the protocol statistical hypothesis, we estimated that the incidence of SCAR would range between 15% and 25% at the 3-month protocol biopsy depending on the treatment arm. This hypothesis was based on the previously reported data, indicating that the incidence of SCAR varied from 15% to 30% during the 3 months posttransplant in patients receiving CsA (15–17). SCAR is defined by the presence of tubulointerstitial inflammatory infiltrates seen on biopsy of renal transplants with stable function. The presence of SCAR has been associated with the progression of chronic tubulointerstitial damage (18) and a reduction in graft survival (19). In our study, contrary to the hypothesis, a SCAR was a rare clinical event in both the AD and FD treatment groups at 3 months (4% vs. 2.5%, respectively) and 1 year (9.3% vs. 10%, respectively). This interesting result indicates that the rate of SCAR probably is overestimated, at least in low-risk patients. Furthermore, in these recipients, the steroids were successfully withdrawn 2 weeks after transplantation. At 1 year, approximately 70% of patients were still free of steroids with a mean estimated creatinine clearance of 49 mL/min and a lower incidence of de novo diabetes and hypertension than in patients receiving corticosteroids in other studies (13, 20).

It has been clearly established that MPA exposure correlates with clinical efficacy in renal transplantation (11, 21), and a therapeutic window for MPA AUC seems to range from 30 to 60 mg · h/L (22) early after transplantation. At the same time, the pharmacokinetics of MPA is characterized by a high between-subject and within-subject variability in part resulting from a low bioavailability early after transplantation (23). Moreover, 50% of patients receiving CsA and 25% of patients receiving tacrolimus (24) and 2 g/d of MMF are underexposed to MPA within the first weeks posttransplant. To overcome this early MPA underexposure, especially in CsA-treated patients, an initial intensified MMF dosing regimen followed by TDM is an approach to consider. In our study, we evaluated this combined strategy: 3 g of MMF for 10 days with subsequent TDM. The results have shown that MPA exposures were significantly higher in the AD group at week 2 and week 6 but similar in both groups at week 12 and thereafter. It is interesting to note that a 50% MMF dose increase only provided a 20% increase in MPA exposure. In contrast, using the same approach in patients receiving tacrolimus, the CLEAR study group (25) reported a 50% increase in MPA exposure. This illustrates that the dose proportionality of MMF in the early period after transplantation is imperfect when MMF is combined with CsA. Furthermore, according to the FDCC study, early adequate exposure (day 3 or 5 posttransplant) is a better predictor of acute rejection (24). Consequently, an initial dose of 4 g for the first 10 days would have been more appropriate in patients receiving CsA. In our study, therapeutic concentrations were successfully achieved by TDM in 65% of patients at week 2 and in 80% at week 6. TDM started at week 2 yielded MMF doses ranging from 1 to 4 g/d at each visit thereafter and significantly reduced the interpatient variability at the week 26 and 52 visits, although, in the FD group, the AUC was more variable than in the AD group. Approximately 14% of patients in the AD group required an MMF dose more than or equal to 3g/d at 1 year after transplantation to reach the therapeutic window. These data suggest that therapeutic concentrations can be achieved easily by the combined strategy of intensified dosing of MMF and subsequent TDM.

In the present study, there was a high rate of physician compliance with the prespecified MMF dose adjustments. Adjustments of the MMF dose were made rigorously in more than 70% of the patients over the study period according to the MPA AUC values measured.

Despite a higher MPA exposure in the AD group, the primary endpoint (the proportion of patients experiencing BPAR or with SCAR identified on the 3-month protocol biopsy) was low and similar between the groups. This suggests that the low rate of BPAR and SCAR at 3 months could not be optimized by TDM in these patients. Still, for recruitment purposes and feasibility, most of the MPA monitoring studies have been performed in low and even very low-risk patients (12, 25, 26). This can explain the controversial results of previous studies. In the APOMYGRE study (12), higher MPA exposure was associated with a reduction of the incidence of acute rejection. In the CLEAR study (25), there was a trend for fewer BPAR episodes in the intensified dosing group (10.2% vs. 25%; P=0.06). In the Fixed-dose Concentration-controlled trial (24), this relationship was less obvious, but a posthoc analysis showed that higher risk patients receiving tacrolimus had rejection rates 2.5-fold more frequently if their day 3 MPA AUC was less than 30 mg · hr/L (27). Taken together, these results suggest that MPA TDM is essential in patients with high immunologic risk, in patients to be treated with calcineurin inhibitor minimization or avoidance protocols and in regimens with steroid avoidance or early withdrawal. For these recipients, greater MPA exposure than currently recommended as the therapeutic window may be needed.

In summary, in renal transplanted patients with low immunological risk, MMF associated with anti-IL-2Rα antibody induction and CsA allows early corticosteroid discontinuation with good tolerability and safety outcomes. MMF 3 g/d administered as maintenance immunosuppression with CsA and MPA TDM guarantees a higher MPA exposure with 80% of patients achieving therapeutic concentrations 3 weeks after transplantation. MMF doses necessary to achieve therapeutic concentrations vary between individuals, suggesting that TDM should be used. In this study, the rates of SCAR at 3 months and 1 year were unexpectedly low and not improved by TDM of MPA.

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MATERIALS AND METHODS

Study Design and Conduct

In this 12-month, prospective, open-label, multicenter study (OPERA trial), de novo renal transplant recipients received anti-IL-2Rα antibody induction followed by a short course of corticosteroid therapy to day 7 posttransplant, MMF (AD or FD) and CsA (C2 monitoring). The study was conducted in 17 centers in France in full compliance with the amended Declaration of Helsinki and the International Conference on Harmonization Harmonized Tripartite Guideline for Good Clinical Practices in the European Community (CPMP/ICH/135/95) and was approved by the Independent Ethics Committee and by the relevant authorities (EUDRACT 2006-000352-41). All study participants provided written informed consent.

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Patient Population

Patients aged 18 to 75 years with low immunologic risk defined as receiving a primary kidney transplant from a deceased or living donor with a current (most recent before transplantation) panel reactive antibody level of 0% and a cold ischemia time less than or equal to 36 hr were eligible for study entry. Key exclusion criteria were receipt of a kidney from a donor older than 70 years, a previous kidney transplant, a combined transplant, and patients with any disease requiring corticosteroid therapy.

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Randomization and Treatment

Eligible patients were randomized into two treatment groups in a 1:1 ratio using a centralized validated system based on a minimization method and were stratified into groups according to center, graft origin, and donor age. All patients received an anti-IL-2R-α antibody, basiliximab, or daclizumab, as induction therapy. CsA was introduced within 72 hr posttransplantation with the dose adjusted to maintain C2 within the following predefined ranges: 1000 to 1500 ng/mL from day 0 to week 4; 800 to 1200 ng/mL from weeks 4 to 12; 500 to 800 ng/mL from weeks 12 to 52.

In the AD treatment group, MMF (CellCept; F. Hoffmann-La Roche, Ltd.) was initiated preoperatively at 3 g/d and then adjusted to a target MPA AUC of 40 mg · h/L. Patients in the FD group received MMF 2 g/d, and investigators were blinded to MPA AUC assessments. If needed, the MMF dose could be adjusted per clinical experience. In both treatment groups, MPA concentrations were measured by high-performance liquid chromatography at weeks 2, 6, 12, 26, and 52. The MPA AUC0–12h was calculated using Bayesian estimations specific for MMF and based on plasma samples drawn at 20 min, 1 and 3 hr after administration (28).

Until day 7 posttransplant, patients in both treatment groups received a corticosteroid comprising intravenous methylprednisolone 500 mg perioperatively followed by oral prednisolone 0.5 mg/kg/d to a maximum of 60 mg/d. Acute rejection was treated with intravenous methylprednisolone according to local practice. Use of antithymocyte antibodies was permitted in cases of steroid-resistant or vascular rejection.

Local practice dictated Pneumocystis jiroveci pneumonia and CMV prophylaxis. CMV prophylaxis for D+/R− patients was mandatory and was in accordance with each center's usual practice.

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Study Endpoints

The primary efficacy endpoint, a composite endpoint at 3 months posttransplant, was the proportion of patients experiencing BPAR on indicated biopsies and those with SCAR identified on the 3-month protocol biopsy. Biopsies were considered clinically indicated when performed in the setting of an increase in serum creatinine level more than 10% from baseline. Protocol biopsies were scheduled at month 3 and 1 year posttransplant. All biopsies were assessed locally, reviewed by a central reading anatomopathologist and classified by an expert reading board according to the 2007 Banff grading schema (29). The secondary efficacy endpoints were the proportion of patients with a BPAR or a SCAR episode at 1 year, renal function as creatinine clearance estimated by the simplified Modification of Diet in Renal Disease method (30) and graft and patient survival.

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Safety Assessments

After initial screening at baseline (day 0), patients returned to the study site for assessments at weeks 2, 4, 6, 12, 16, 26, 39, and 52. All adverse events were recorded irrespective of severity or relationship to the study medication, with special attention to the following: anemia (hemoglobin level <10 g/dL, excluding the first month posttransplant or evident blood loss); leukopenia (total white cell count <2×109/mL); gastrointestinal adverse events (diarrhea, constipation, anorexia, abdominal pain, nausea, or vomiting); and infections (including CMV and herpes). New onset diabetes mellitus was defined by the 2003 diagnostic criteria for the American Diabetes Association or de novo prescription of hypoglycemic therapy (31).

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Statistical Analysis

The primary efficacy analysis population, the intention-to-treat population, included all patients who were randomized, who received at least one dose of MMF and who underwent kidney transplantation. The safety population included all randomized patients who received at least one dose of study medication.

Descriptive statistics summarized demographic and baseline variables. The principal efficacy analysis compared the composite endpoint during the first 3 months between the two groups using a chi-square test. Between-group comparisons for secondary endpoints were performed using Student's t test, variance analysis, Wilcoxon's rank-sum test, the chi-square, or Fisher's exact test, as appropriate. Safety was analyzed in terms of adverse events, changes in vital signs (weight, clinical signs), and laboratory test results. Statistical analyses were performed with a two-sided significance level of 5% using SAS software version 9.1 (SAS Institute, Cary, NC).

The sample size was calculated to provide 90% power with α=5% (two-sided) to detect a between-group difference of 20% in the proportion of patients with BPAR or SCAR during the first 3 months of treatment favoring the AD treatment group (AD group: 20% comprised 5% of BPAR and 15% of SCAR episodes vs. the FD group: 40% comprised 15% of BPAR and 25% of SCAR episode). According to these hypotheses, 128 patients per group were to be randomized.

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ACKNOWLEDGMENTS

The authors acknowledge the contributions made by all physicians and site study staff, all local anatomopathologists, the centralized reading board in particular L.H. Noël, all local laboratory scientists, the Limoges Inserm Unit for Mycophenolic Acid Therapeutic Drug Monitoring in particular P. Marquet, the study advisory board, the DSMB, the project team for study management, and Francoise Allano (Roche SAS, France) for her great contribution to the study. They also thank the Zola Associates, Englewood Cliffs, NJ, for the editorial support.

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Keywords:

Early corticosteroid withdrawal; Kidney transplantation; Mycophenolate mofetil; Therapeutic drug monitoring

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