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Table of Contents
ORIGINAL ARTICLE
Year : 2019  |  Volume : 2  |  Issue : 2  |  Page : 82-87

Mycophenolate mofetil for maintenance of remission in children with steroid- and calcineurin inhibitor- dependent nephrotic syndrome: A prospective, randomized multicenter trial


1 Department of Pediatrics, Chonnam National University and Children's Hospital, Gwangju, South Korea
2 Department of Pediatrics, Hallym University Kangnam Sacred Heart Hospital, Cheongju-si, Chungcheongbuk-do, South Korea
3 National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Cheongju-si, Chungcheongbuk-do, South Korea
4 Department of Pediatrics, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
5 Department of Pediatrics, Yeungnam University College of Medicine, Yeungnam University Hospital, Daegu, South Korea
6 Department of Pediatrics, Jeju National University, School of Medicine, Jeju, South Korea
7 Department of Pediatrics, Jang's Women's Hospital, Yangsan, South Korea
8 Department of Pediatrics, Pusan National University Children's Hospital, Yangsan, South Korea
9 Department of Pediatrics, Seoul National University Children's Hospital; Department of Pediatrics and Kidney Research Institute, Seoul National University College of Medicine, Seoul, South Korea

Date of Web Publication4-Dec-2019

Correspondence Address:
Hee Gyung Kang
Hae IlSeoul National University Children's Hospital and Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-Gu, Seoul 03080
South Korea
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/AJPN.AJPN_10_19

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  Abstract 


Background: Mycophenolate mofetil (MMF), a nonsteroidal immunosuppressive agent, has been used as a therapeutic option in various immune-mediated glomerulonephritis. However, controlled studies that examine the efficacy of MMF monotherapy in steroid- and calcineurin inhibitor (CNI)-dependent nephrotic syndrome (NS) are lacking. Aim: This study assessed the efficacy and safety of MMF monotherapy in children with steroid- and CNI-dependent NS. Methods: In this prospective, randomized, open-label, multicenter pilot study, we evaluated the efficacy and safety of MMF after CNI and corticosteroid therapy in children with steroid-dependent NS. We compared the duration and timing of sustained remission between patients managed with or without MMF and monitored for adverse effects of MMF. Statistical Analysis Used: The data were analyzed using standard statistical tests on the modified intention-to-treat population. Results: The baseline characteristics between the two groups did not differ significantly. There was neither difference in the duration of the sustained remission between patients in the MMF and control groups (4.2 ± 3.5 months vs. 3.8 ± 3.4 months, respectively; P = 0.772) nor in the proportion in sustained remission after 12 months (P = 0.936). Patients received MMF did not experience significant toxicity; chiefly, self-remitting gastrointestinal adverse events were observed. Conclusions: Therapy with MMF is safe but ineffective in influencing rates of remission in patients with NS dependent on steroids and CNIs.

Keywords: Minimal change disease, mycophenolate mofetil, steroid-sparing frequent relapses


How to cite this article:
Yang EM, Park E, Choi HJ, Hyun H, Park Yh, Han KH, Park H, Kim SH, Ha IS, Il Cheong H, Kang HG. Mycophenolate mofetil for maintenance of remission in children with steroid- and calcineurin inhibitor- dependent nephrotic syndrome: A prospective, randomized multicenter trial. Asian J Pediatr Nephrol 2019;2:82-7

How to cite this URL:
Yang EM, Park E, Choi HJ, Hyun H, Park Yh, Han KH, Park H, Kim SH, Ha IS, Il Cheong H, Kang HG. Mycophenolate mofetil for maintenance of remission in children with steroid- and calcineurin inhibitor- dependent nephrotic syndrome: A prospective, randomized multicenter trial. Asian J Pediatr Nephrol [serial online] 2019 [cited 2020 May 30];2:82-7. Available from: http://www.ajpn-online.org/text.asp?2019/2/2/82/272303

FNx01These authors contributed equally.





  Introduction Top


Most children with nephrotic syndrome (NS) respond well to corticosteroids, but 80% of them experience disease relapses, often frequently and over several years, leading to corticosteroid adverse effects.[1] Calcineurin inhibitors (CNIs) have excellent steroid-sparing potential but are associated with significant adverse effects,[2] and nephrotoxicity limits their long-term use. However, the discontinuation of CNI usually results in frequent relapses or steroid dependence. Further, 10%–20% of patients with steroid-dependent NS (SDNS) continue to relapse frequently while receiving CNI.[3],[4] Therefore, effective and safe alternative therapies are needed for managing CNI and SDNS.

Mycophenolate mofetil (MMF), an ester prodrug of the immunosuppressant mycophenolic acid, is commonly used for maintenance immunosuppression in pediatric renal transplant recipients and various glomerulonephritis.[5],[6],[7] Based on observational studies indicating the reduced frequency of relapses and prednisolone requirement and high rates of sustained remission, the Kidney Disease: Improving Global Outcomes and other expert groups also recommend its use in patients with NS experiencing steroid toxicities.[8],[9],[10],[11],[12],[13],[14] However, there are no randomized controlled trials (RCTs) examining the efficacy of MMF monotherapy compared to no therapy or placebo. The present study was a pilot study of efficacy and safety of MMF as maintenance immunosuppression in children with steroid- and CNI-dependent NS, as compared to controls.


  Methods Top


This prospective, randomized, open-label, multicenter, pilot controlled trial was conducted at six major pediatric nephrology centers in Korea to examine the efficacy and safety of MMF, compared to no therapy, over a period of 12 months in patients with steroid- and CNI-dependent NS. The study protocol was approved by the institutional review board at each participating clinical center and by the Korean Ministry of Food and Drug Safety Seoul National University Children's Hospital (IRB No. 1305-582-489) and registered at http://clinicaltrials.gov (NCT01895894). All participants provided written informed consent after being informed of the study proposal, duration, procedures, alternatives, risks, benefits, and their rights to withdraw from the study at any time.

Eligibility

Children older than 2 years, with SDNS and steroid-sensitive relapse(s) during the past year despite ongoing therapy with CNI for over 1 year, and with complete remission, were eligible to participate in the study. Patients were excluded if they had hereditary or secondary NS, history of acute hepatitis or gastrointestinal disease, estimated glomerular filtration rate <60 mL/min per 1.73 m2, and/or had previously received treatment with MMF.

Randomization

Following enrollment during disease remission, patients were randomly allocated to receive either MMF or no therapy (control group) for 12 months, or until relapse, whichever was earlier. Randomization was conducted using a centralized, web-based randomization system managed by the Medical Research Collaborating Center (MRCC, https://mrcc.snuh.org) of Seoul National University Hospital and used permuted block randomization with a concealed and varying block size. Participants were randomly allocated in a 1:1 ratio to either receive or not receive MMF. The randomization list was preserved with the MRCC and was not accessible to the investigators until the end of follow-up of the last patient. Neither participants nor investigators were blinded to the treatment allocation.

Therapy

Following randomization, the dose of alternate-day prednisolone, if being administered, was tapered by 10 mg/m2 or 0.375 mg/kg every 4 weeks from the start of the study. CNI was tapered by 25% every 4 weeks to discontinue over 12 weeks. Tapering of CNI was initiated once prednisolone was discontinued in patients receiving steroids at enrollment, and at randomization, for those not receiving steroids at enrollment. In patients randomized to MMF, therapy with Myrept® (Chong Kun Dang Pharmaceutical Corporation, Seoul, Korea), was initiated at randomization at a dose varying from 12.8 to 31.3 mg/kg in two divided doses for 2 weeks, and subsequently increased, if no adverse events were observed, to 23–33 mg/kg/day, with a maximum dose of 750 mg twice daily [Table S1]. Therapy with MMF was continued for 12 months or until relapse occurred, whichever was earlier.



The dose of MMF was reduced stepwise, as shown in [Table S1], in the presence of gastrointestinal adverse events, low hematocrit (<25%), or neutropenia (absolute neutrophil count <1000/mm3). If the abnormality persisted for more than 2 weeks, the MMF dose was reduced again in accordance with step 2 of the protocol. Therapy with MMF was discontinued if the problem persisted for more than 2 weeks after step 2 reduction [Table S1].[15] The levels of MMF were not monitored. No additional immunosuppressive agents other than steroids were allowed during the study period. Angiotensin-converting enzyme inhibitors and other antihypertensive or lipid-lowering agents were added to the regimen when necessary.

Follow-up

For the first 3 months after randomization, patients were followed up monthly, with additional visits, every 14–21 days, for dose titration in patients randomized to receive MMF, until the protocol-recommended MMF dose was achieved. At each visit, records maintained by parents were reviewed for relapses, medications, infections, adverse events, and for protocol-defined efficacy and safety parameters. Treatment adherence to the intervention was assessed by pill count of the returned packs. Parents of patients were instructed to record urine protein values using urine dipstick, twice a week, at home. At each visit, we examined the urine protein-to-creatinine ratio in the first-morning urine sample, the blood levels of blood urea nitrogen, creatinine, albumin, electrolytes, cholesterol, liver function tests, and blood counts. After 3 months, patients were followed up every 3 months until a relapse occurred or until end of the study at 12 months. The study participation was terminated, earlier than 1-year follow-up period, at relapse, in the patients with occurrence of relapse before the end of follow-up.

Outcomes

The primary outcome was a comparison of the duration of sustained remission during 12-month follow-up in the two groups. A relapse was defined as the reappearance of dipstick urine protein more than 2+, or urine protein/creatinine ratio more than 2.0, for 3 consecutive days. The duration of sustained remission was defined as the duration from randomization to the occurrence of relapse. The secondary outcome was the proportion of patients in remission at 3, 6, 9, and 12 months of follow-up. Safety assessments included clinical and laboratory evaluation and monitoring for adverse events. Adverse events that required hospitalization or resulted in persistent or significant disability or incapacity were considered serious and were reported to the ethics committee within 24 h.

Statistical analysis and sample size

Data were analyzed on a modified intention-to-treat population that included all patients who returned for their first follow-up. Categorical variables were analyzed using the Fisher's exact or Chi-square tests. Continuous variables were presented as median or mean ± standard deviation, based on data distribution, and were analyzed using the independent samples t-test or the Mann–Whitney U-test. We used the Kaplan–Meier method with the log-rank test to compare the duration of sustained remission between patients in MMF and control groups. All statistical analyses were performed using IBM SPSS statistics for Windows, version 20.0 (IBM Corp. Released 2011; IBM Corp., Armonk, NY, USA).

As this was a pilot study, we followed rule of thumb suggested as appropriate in literature for pilot studies.[16] To compensate for expected dropouts, we aimed at enrolling at least 30 patients into the trial.[16]


  Results Top


Baseline characteristics

Of 34 patients with steroid- and CNI-dependent NS enrolled during 2013–2016, 16 were randomized to receive MMF and 18 were randomized to the control limb [Figure 1]. The baseline characteristics of randomized patients are shown in [Table 1]. The two groups of patients did not differ in the age at the onset of disease and enrollment, or in the relapse rate within a year prior to the study, duration of CNI usage, and doses and type of current immunosuppression.
Figure 1: Study flow

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Table 1: Demographic and clinical characteristics of the patients at the baseline

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Outcomes

All patients, except for two patients randomized to control limb for whose no data were available after randomization, were included in the modified intention-to-treat analysis. Protocol violations were observed in both the groups; two patients in the MMF group and one case in the control group did not follow the scheduled steroid-tapering protocol.

One (6.3%) patient in each group showed sustained remission over 12 months during the study. Patients randomized to MMF and control limbs showed a similar duration of sustained remission (4.2 ± 3.5 months vs. 3.8 ± 3.4 months, respectively; P = 0.77) [Figure 2]. The proportion of patients with sustained remission in the MMF and control groups were similar at 3 months (50% each; P = 0.82), 6 months (18.8% vs. 25.0%; P = 0.82), 9 months (12.5% vs. 6.3%; P = 0.83), and 12 months (6.3% vs. 6.3%; P = 0.94) [Figure 3]. Patients in MMF and control groups did not show statistically significant differences in the duration of therapy with prednisolone (3.0 ± 2.3 months vs. 2.1 ± 1.1 months; P = 0.47) and CNI (3.9 ± 2.9 months vs. 3.6 ± 2.4 months; P = 0.87) after randomization.
Figure 2: There was no significant difference in the duration of sustained remission between the control and mycophenolate mofetil groups (P = 0.772)

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Figure 3: Relapse-free survival rate up to 12 months for patients in the mycophenolate mofetil group (MMF, n = 16) and control group (n = 16). The log-rank test showed that the curves did not significantly differ (P = 0.936)

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Adverse events

Adverse events related to therapy with MMF were generally mild, and most patients tolerated therapy well. One patient had abdominal pain, elevated liver enzymes, and weight loss, which resolved after stopping MMF for 2 weeks; symptoms did not recur after MMF therapy was resumed. Another patient had nausea, dizziness, and elevated bilirubin; these resolved after the dose reduction. One patient had transient abdominal pain and another had transient loose stools; dose modification was not necessary in either patient.


  Discussion Top


In this RCT, we enrolled 34 children with NS dependent on both steroids and CNI who had relapsed during the therapy with CNI. We aimed to investigate the effect of MMF to maintain disease remission while steroids and CNI were tapered and discontinued. We found that MMF was well tolerated; however, it was not effective in maintaining disease remission in children with steroid- and CNI-dependent NS.

While therapy with corticosteroids is successful in patients with SDNS, long-term use of steroids leads to Cushingoid appearance, hypertension, cataract, and growth failure.[17] Patients with multiple relapses, steroid toxicity, and high steroid exposure require alternative therapy. Since the use of cyclosporine in patients with steroid-dependent and steroid-resistant NS in the last two decades,[1],[18],[19] there is a reduced incidence of steroid toxicities. Evidence from several RCTs indicate that CNIs are effective;[20],[21],[22] however, consensus is lacking about the optimal duration of use. Guidelines suggest continuing therapy for 1 year or longer in patients who show complete or partial remission. However, the long-term use of CNIs is limited by their nephrotoxicity. Alternative therapies that are effective and safe for children with persistent relapses after therapy with CNI have not been identified.

Several reports suggest that switch to MMF is useful in patients with SDNS receiving prolonged treatment with CNI.[13],[23] MMF, a purine antagonist that selectively inhibits the proliferation of T- and B-lymphocytes, has proven efficacy and tolerability in organ transplantation.[24] Its efficacy in children with NS was first reported in 2000,[25] followed by a pilot study in children with difficult NS in 2003.[23] Several uncontrolled studies have shown that MMF reduces prednisolone requirement in SDNS, with high rates of sustained remission and lower relapse rates as compared to those during the previous treatment period with corticosteroids or in patients switched from cyclosporine.[8],[9],[12],[13] Three RCTs reveal that MMF is beneficial in SDNS but is less effective than CNIs.[26],[27],[28] The present RCT intended to determine the efficacy and safety of MMF monotherapy compared to no therapy in children with CNI-dependent SDNS. We found no significant differences in time to relapse and rates of relapse-free survival, at three monthly intervals, during 12 months of therapy with MMF or no drug. The lack of efficacy of MMF in the present RCT may be because of the differences in enrollment criteria or due to the fact that ours was a small study with limited statistical power. However, these results support findings of an RCT from Germany that showed MMF to be inferior to cyclosporine A in preventing relapse in pediatric patients with frequently relapsing NS.[27]

While the present study failed to show the efficacy of MMF in maintaining remission in children with steroid- and CNI-dependent NS, it highlights its safety. MMF has low systemic toxicity and is reported to be tolerated well in patients with NS.[10] Reported adverse effects are mostly mild or transient and chiefly include gastrointestinal disturbances (abdominal pain and diarrhea), infections, and hematological abnormalities such as anemia, lymphopenia, or thrombocytopenia.[12],[14],[26] Few patients have had to discontinue MMF.[10] The incidence of gastrointestinal symptoms has varied from 3.1% to 11.5% in studies including 96–340 patients.[29],[30] In the present study, four (30%) children had such symptoms and two required dose reduction in view of elevated liver enzymes or bilirubin levels. We did not observe hematologic abnormalities. Overall, symptoms were transient and resolved completely. However, it is possible that adverse effects, particularly infections, are more common or severe when MMF is given in combination with other immunosuppressive agents.[31],[32]

Our study has some limitations. First, the small sample size does not provide sufficient statistical power to reach meaningful conclusions. However, the results of our study are consistent with the findings of relatively lower efficacy of MMF in sustaining remission in children with CNI-dependent SDNS in previous studies.[8],[21] Second, we did not monitor the pharmacokinetics of mycophenolic acid. Over the past decade, studies have reported that achieving certain area under the curve values for MPA levels is associated with reasonable efficacy; however, we used MMF in doses similar to those used in previous reports where steroid-sparing effects with reduction of relapses were achieved without significant toxicity[10],[11], providing assurance of its pharmacokinetic adequacy.[11],[33] Third, it is possible that there were better dose-tapering schedules for steroid and CNI than were followed by us. Fourth, the limited duration of follow-up might have biased the assessment of safety of MMF.


  Conclusions Top


This pilot study shows that treatment with MMF is safe but may not be effective in children with steroid- and CNI-dependent NS. Future, adequately powered, large-scale, prospective trials are needed to examine the relative efficacy of MMF, compared to placebo or rituximab, another agent that has been reported to have promising results for the therapy of complicated SDNS.[34] Despite the limitations of this RCT, we believe that our results provide useful information to future studies seeking equally effective but less toxic therapies in NS.

Acknowledgment

This study was supported by a grant of the Korea Health Technology Research & Development Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of Korea (Grant number: HI18C0013).

Financial support and sponsorship

This study was supported by Chong Kun Dang Pharmaceutical Corporation, Seoul, Republic of Korea. Chong Kun Dang Pharmaceutical Corporation manufactures Myrept® (Mycophenolate mofetil) and Cipol-N® (Microemulsion cyclosporine).

Conflicts of interest

There are no conflicts of interest.



 
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