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Published ahead of print on October 4, 2006
Clin J Am Soc Nephrol 1: 1173-1178, 2006
© 2006 American Society of Nephrology
doi: 10.2215/CJN.00550206
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Clinical Nephrology

Mycophenolate Mofetil in Children with Frequently Relapsing Nephrotic Syndrome: A Report from the Southwest Pediatric Nephrology Study Group

Ronald J. Hogg*, Lisa Fitzgibbons{dagger}, Joy Bruick{dagger}, Martin Bunke{ddagger}, Bettina Ault§, Noosha Baqi||, Howard Trachtman, and Rita Swinford**

* St. Joseph’s Hospital and Medical Center, Phoenix, Arizona; {dagger} Department of Clinical Research, Medical City Dallas Hospital, Dallas, Texas; {ddagger} Roche Laboratories, Nutley, New Jersey; § University of Tennessee, Memphis, Tennessee; || State University of New York Brooklyn, Brooklyn, New York; Schneider Children’s Hospital, New Hyde Park, New York; and ** University of Texas-Houston, Houston, Texas

Address correspondence to: Dr. Ronald J. Hogg, SPNSG Central Office, St. Joseph’s Hospital & Medical Center, 222 W. Thomas Road, Suite 410, Phoenix, AZ 85013. Phone: 800-345-4426; Fax: 602-406-3976; E-mail: spnsg{at}chw.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Children with frequently relapsing nephrotic syndrome (FRNS) often develop adverse effects from prednisone. Attempts to induce long-term remission in such patients have had varying levels of success. In this multicenter, prospective, open-label study, 14 centers enrolled 33 patients with FRNS, all of whom were in remission at the time of entry. Six of the patients were steroid dependent. The patients received mycophenolate mofetil (MMF) 600 mg/m2 twice daily (maximum 1 g twice daily) for 6 mo. A tapering dosage of alternate-day prednisone was given to each patient during the first 16 wk of MMF therapy. Patients were monitored for relapses of NS during and after MMF therapy. Treatment failure was defined as a relapse of NS. The patients had the following features at study entry: Age 6.8 ± 2.7 yr (range 2 to 15 yr); 56% male, 44% female; and 50% white; 25% black, and 25% other. Estimated GFR at entry was 138 ± 42 ml/min per 1.73 m2. Twenty-four (75%) of 32 patients stayed in remission throughout the 6 mo of MMF therapy. The relapse rate in these patients improved from one episode every 2 mo before MMF to one every 14.7 mo after MMF. Eight patients stayed in remission during the post-MMF period, for periods of 18 to 30 mo, whereas 16 relapsed after stopping MMF. Eight (25%) of 32 patients relapsed while taking MMF. It is concluded that MMF is effective for maintaining remission in patients who have FRNS and receive treatment for at least 6 mo and is associated with a low incidence of adverse events.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Frequently relapsing nephrotic syndrome (FRNS) in children and adults represents a difficult condition that often confronts nephrologists. Many patients with FRNS can be maintained in remission on continuous treatment with corticosteroids or cyclosporine A (CsA) but go into relapse when such treatment is discontinued. However, physicians and patients have become increasingly reluctant to use steroids or CsA for prolonged periods because of the risk for adverse events. Corticosteroids are associated with significant toxicity when given repetitively in large dosages. This is particularly true in small children, in whom severe growth impairment often is seen after long-term corticosteroid therapy. CsA is associated with nephrotoxicity in some patients. Preliminary data from a series of pediatric (1–8) and adult (9–11) studies suggest that mycophenolate mofetil (MMF) may represent a less toxic alternative for patients with FRNS. Other recent studies have reported that mizoribine (12–17) or levamisole (18) also may be options to consider in such patients.

Our study was designed to evaluate the safety and the efficacy of MMF for children who had FRNS and had not been exposed to other immunosuppressive drugs. All patients were in remission when they entered the study. The primary goal was to determine whether freedom from relapse of NS would be enhanced by MMF, both during and after the period of therapy.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patient Population
Patients who were aged 2 to 20 yr were eligible for entry into this study when they had evidence of either steroid-dependent NS (SDNS) or FRNS. Relapse of NS before study entry was defined as proteinuria ≥2+ by dipstick for 3 or more consecutive days or recurrence of sufficient clinical features of NS to prompt therapy with daily steroids by the attending physician.

SDNS was defined in patients who had a relapse of NS after a decrease in the dosage of prednisone or within 28 d of stopping prednisone on two or more consecutive occasions in the 12 mo before entry. One of these episodes must have been within 3 mo before entry. FRNS was defined in patients who responded to prednisone treatment but who had four or more relapses within the 12 mo before the screening visit or two or more relapses within the first 6 mo after the initial response (if this was in the 6 mo before entry).

Patients were allowed to receive a course of cyclophosphamide or chlorambucil in the past but again had to satisfy the entry criteria for steroid dependence and/or FRNS after the course of cytotoxic medication was completed. Female patients of childbearing potential were required to have a negative pregnancy test <1 wk before starting MMF. Such patients had to agree to use two reliable forms of contraception simultaneously before beginning study drug therapy, during therapy, and for 6 wk after discontinuation of study drug therapy.

Exclusion criteria that were used in the study included the following: Absolute neutrophil count (ANC) <2000/mm3; hematocrit <25%; estimated GFR <50 ml/min per 1.73 m2 at time of study entry (19); history of significant gastrointestinal disorder; active systemic infection or history of serious infection within 1 mo of entry; known infection with HIV or the presence of hepatitis B surface antigen; other major organ system disease or malignancy; current or previous treatment with MMF, azathioprine, levamisole, FK506, or CsA; pregnancy or breast feeding at time of entry or unwillingness to comply with measures for contraception described above; administration of live viral vaccine within 6 wk before study entry; and current or recent (within 30 d) exposure to any investigational drug.

Study Design/Medications
Patients who fulfilled all of the entry criteria and had none of the exclusion criteria received a 28-wk course of MMF in liquid form (concentration of 200 mg/ml). They also received a tapering 16-wk course of alternate-day prednisone when the MMF first was given (this was stopped in all patients at week 16). At the end of 24 wk of treatment, the dosage of MMF was reduced by one third every 2 wk. The individual dosage of MMF was determined by the patient’s body surface area. Each patient received an initial dosage of 600 mg/m2 twice daily (up to a maximum of 1 g twice daily). Prednisone or prednisolone was prescribed at a dosage of 1 mg/kg every other day (maximum dosage 40 mg every other day) during the first 8 wk of MMF. This was followed by 0.5 mg/kg every other day (maximum dosage 20 mg every other day) for the second 8 wk (weeks 9 through 16).

Management of Adverse Events
If a patient developed gastrointestinal toxicity or hematocrit was <25% or ANC was 1000 to 1500, then the dosage of MMF was reduced to 400 mg/m2 twice daily. If after 1 wk gastrointestinal toxicity continued or either of these laboratory studies remained abnormal, then the dosage of MMF was reduced to 200 mg/m2 twice daily. If any of these problems persisted subsequently, then MMF was stopped. In a case of severe toxicity, more rapid reduction of MMF by the participating investigator was allowed. If ANC was <1000, then MMF was stopped immediately. No prednisone was given during the final 12 wk of MMF therapy.

Patient Monitoring
Urine protein was monitored at home by dipstick. Treatment failure was defined as a relapse of NS (i.e., presence of edema or ≥2+ proteinuria for ≥3 d, plus central laboratory urine protein/creatinine ratio ≥1.0 on first morning urine or serum albumin <3.0 g/dl). If a patient had proteinuria at home but central laboratory studies did not confirm relapse, then the patient continued MMF.

Statistical Analyses
Clinical data were collected by study coordinators on case report forms in each participating site and then forwarded to the Administrative Coordinating Center in Dallas. Data were checked for accuracy by coordinators at the Administrative Coordinating Center before being entered into the database. Data are expressed as mean ± SD unless otherwise stated. The average number of relapses before and after MMF therapy was determined. A Wilcoxon ranks test was applied to determine whether there was a significant change in relapse rate before and after therapy with MMF.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Thirty-three patients with FRNS were enrolled into the study (Figure 1). Six of these patients were steroid dependent. MMF was discontinued in one patient when he had a relapse after only 2 d of therapy, and this patient is not considered further in the results. The other 32 patients had the following features at the time of study entry: Age 6.8 ± 2.7 yr (range 2 to 15 yr); 56% male, 44% female; and 50% white; 25% black, and 25% other. Estimated GFR at entry was 138 ± 42 ml/min per 1.73 m2. All patients had a normal serum albumin at entry and throughout the subsequent follow-up until relapse of the NS developed.


Figure 1
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  		Figure 1. Flow diagram of the course of the 33 patients who were enrolled in the study.

 
Efficacy of MMF
Twenty-four (75%) of 32 patients stayed in remission throughout the 6 mo of MMF therapy. Twelve of these patients subsequently stayed in remission for at least 6 mo after discontinuation of MMF (MMF-sensitive patients), whereas 12 patients relapsed in the 6 mo after stopping MMF (MMF-dependent patients). Subsequent follow-up revealed that eight of the MMF-sensitive patients remained in remission with no treatment, whereas 4 had a relapse of their NS (Table 1). Eleven of the 16 patients who had a relapse after MMF were restarted on MMF by their primary nephrologists at some stage after study; five subsequently have stayed in remission, and six had infrequent relapses (fewer than four per year; Figure 1). Only eight (25%) of 32 patients relapsed while on MMF (five relapsed while on both prednisone and MMF during the first 3 mo of study, and the other three relapsed while on MMF alone, during the second 3 mo of study). Relapse data, collected before and after MMF treatment over varying time periods, then were normalized to estimate the number of relapses per 12 mo in each patient. Preintervention relapse data were available for all patients.


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  		Table 1. Details of MMF-sensitive patients (n = 12)a

 
MMF-Sensitive Patients
Patients who remained relapse-free for at least 6 mo after the end of MMF therapy have been denoted as having MMF-sensitive NS. Details of these 12 patients are given in Table 1. The patients ranged in age from 3 to 10 yr (mean 6.7 ± 2.0 yr), and 58.3% were boys. Their annualized relapse rate of NS was 6.0 ± 2.3 per year before MMF and 0.47 ± 0.76 per year after MMF (P < 0.01). The period of follow-up after the time when MMF was given ranged from 18 to 31 mo in these patients.

MMF-Dependent
The MMF-dependent patients were defined as those who remained in remission throughout the time they were receiving MMF but relapsed in the 6-mo period after this therapy was discontinued. Details of these patients are provided in Table 2. They ranged in age from 2 to 15 yr (mean 6.2 ± 3.3 yr), and 50% were boys. The annualized relapse rate in these 12 patient was 7.4 ± 2.6 per year before MMF. The patients stayed in remission for an average of 61 d after MMF (range 10 to 144 d). Accurate follow-up data for periods of 11 to 18 mo after MMF relapse were available in nine of the patients. In these patients, the annualized relapse rate of NS was 8.1 ± 3.0 episodes per year before MMF and 1.1 ± 1.0 per year after MMF (P = 0.02). It should be noted, however, that nine of the 12 patients in this group were re-treated with MMF by the pediatric nephrologists after they exited the study.


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  		Table 2. Details of MMF-dependent patients (n = 12)

 
MMF-Resistant Patients
Eight patients (25% of the total) were defined as MMF resistant because they developed a relapse of NS while they were still being treated with MMF. These patients ranged in age from 2 to 11 yr (mean 6.3 ± 3.4 yr), and 62.5% of them were boys. Five of the patients relapsed within 2 mo of starting MMF. It perhaps is noteworthy that in four of these patients, the attending pediatric nephrologist commented on lack of compliance and/or limited follow-up. However, the relevance of these observations cannot be validated by objective data. Three of these patients relapsed 3 to 10 wk after they were taken off prednisone. The annualized relapse rate of NS in the eight MMF-resistant patients before MMF was 8.0 ± 3.3 per year. There were insufficient data to calculate accurately the post-MMF relapse rates in these patients.

Overall Change in Relapse Rate after MMF
Although accurate relapse data were available for all MMF-resistant and -dependent patients before and during the trial, such data were available only for 21 of these patients after the study (as depicted in the final columns of Tables 1 and 2). The NS relapse rate was 1 per 1.97 patient-months before MMF and 1 per 14.7 patient-months after MMF in these patients. However, it is clear that these data are not representative of the entire cohort of patients, and it is apparent from Table 2 that this level of success in the MMF-dependent patients was associated with additional courses of MMF in some patients.

Adverse Events
Only two serious adverse events were recorded during the study. One patient permanently stopped MMF because of an ANC of 300/mm3. Within 8 d, her ANC normalized to 4600/mm3. Four other patients had mild decreases in the ANC. This was transient in each case and not associated with any clinical problems. Another patient was hospitalized for a varicella outbreak while on MMF. He recovered without incident. In one case, it was concluded that the low ANC was secondary to specimen damage during shipping to the central laboratory. One patient started on an H-2 blocker for gastritis during MMF therapy, but gastrointestinal complaints were surprisingly rare in our patients. Details of all of the adverse events that were seen in the patients in this study are given in Tables 1 through Go3.


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  		Table 3. Details of MMF-resistant patients (n = 8)

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our results show that MMF is an effective agent for maintaining remission in patients who have FRNS and receive treatment for at least 6 mo and is associated with very few adverse events. Seventy-five percent (24 of 32) of our patients stayed in remission while receiving MMF, and the relapse rate in these patients fell from one relapse every 2 mo before MMF to one relapse every 14.7 mo after MMF. However, in keeping with other recent studies of MMF in patients with FRNS and/or SDNS, the study suffered from lack of placebo-controlled design. Hence, we must interpret the results with some caution.

The use of MMF in children with NS first was described in 1999 in a preliminary report at the Annual Meeting of the American Society of Nephrology. Bartosh et al. (1) empirically treated five children who had NS and whose mean age at presentation with NS was 4.0 ± 1.7 yr. Three of the patients were steroid dependent; two were partially responsive to prednisone. The mean dose of MMF was 892 ± 197 mg/m2 per d (range 667 to 1163 mg/m2 per d). The authors reported that one of the children achieved steroid-free remission; two had improvements in their clinical status. Adverse effects were rare, although one child experienced moderate gastrointestinal distress. Subsequent reports of the use of MMF in children with FRNS and/or SDNS are summarized in Table 4. It should be noted, however, that considerable variation exists between these reports with regard to the patient populations being studied and the dosage/duration of MMF that was used.


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  		Table 4. Previous reports of MMF in children with idiopathic nephrotic syndromea

 
Barletta et al. (2) reported their experience with MMF in four children who had FRNS or SDNS. The patients ranged in age from 2 to 5 yr when they presented with NS and from 3 to 12 yr when MMF was started. Renal biopsies were obtained in all of these patients; three patients had minimal-change disease, and one had IgM nephropathy. The dosage of MMF that was given was 800 to 1200 mg/m2 per d. All four patients had previously received a 12-wk course of cyclophosphamide. The patients had a reduction in the frequency of relapses during MMF treatment (from 4.25 relapses per year in the year before MMF compared with 1.75 relapses per year on MMF; P = 0.06). Two of their patients experienced gastrointestinal adverse effects, but none had leukopenia. These authors also described a beneficial effect with MMF in 10 patients who had NS and were CsA dependent in the same publication.

In the largest study of MMF in children with NS reported to date, Bagga et al. (3) studied the efficacy of a 12-mo course of MMF in 19 children with SDNS. Their population differed from the patients in our study in that most of them had been exposed to cyclophosphamide and/or levamisole before a trial of MMF was instituted. All of the patients were classified as steroid dependent, as defined in the Materials and Methods section of this article. The authors reported a significant decrease in the relapse rate while the patients were receiving MMF, but this effect was not sustained after the therapy was discontinued. The MMF was dispensed as 500-mg tablets, but it was not clear how these were administered to achieve a dosage of 20 to 25 mg/kg per d in each patient. The primary adverse effects were minor gastrointestinal disturbances, which were not evident in our patients, perhaps because our patients received the liquid formulation of MMF. In contrast, Bagga et al. reported no instances of leukopenia in their patients, whereas this was observed in five of our patients, although only one of our patients had a confirmed ANC <1000. We believe that the patients reported by Bagga et al. had "more dependent" NS than ours and certainly had been afflicted with the NS for longer periods of time. This may explain why their patients, although responding well to MMF, did not show the level of benefit that was seen in our patients.

In 2004, Gellermann et al. (4) reported that MMF was highly effective in seven children who were aged 9 to 16 yr and were both steroid and CsA dependent. These patients all had signs of nephrotoxicity after long courses of CsA therapy. The initial dosage of MMF, which was 500 mg/m2 twice daily, was adjusted to give blood trough mycophenolic acid levels of 1.5 to 4.5 µg/ml. The duration of therapy was 25 mo (range 15 to 39 mo), during which time six (85%) of seven of the patients remained in remission. In addition, the GFR rose after the patients were switched from CsA. There was no report of leukopenia or gastrointestinal adverse effects. These impressive results, albeit in a small number of children, were very similar to those that were obtained in our patients, 75% of whom were relapse-free while on MMF. In 2005, Novak et al. (5) conducted a retrospective review of 21 patients who were aged 2 to 17 yr and had SDNS. Four of the patients had received cyclophosphamide, and five had received CsA. The dosage of MMF that was given was 600 mg/m2 twice daily (maximum dosage 1 g twice daily). Duration of treatment was 1.0 ± 0.5 yr. The NS relapse rate fell from 9.6 to 5.6 per year while on MMF (P < 0.02). No post-MMF data were provided in this patient population.

The potential benefit of MMF in children who have NS, are both steroid and CsA dependent, and have signs of nephrotoxicity also has been the subject of some recent studies. In 2005, Ulinski et al. (6) reported their findings in 9 children who were aged 3 to 16 yr. These patients had CsA-dependent NS, or steroid-resistant NS, and CsA nephrotoxicity. Each of the patients was switched from CsA to MMF. The dosage of MMF was up to 1 g/1.73 m2 twice daily. The length of follow-up was 261 ± 183 d. The authors reported that (1) patients with SDNS stayed in remission, (2) patients with steroid-resistant NS had no change in level of proteinuria, (3) GFR increased from 76 ± 5 to 119 ± 6 ml/min per 1.73 m2, and (4) no significant adverse events were encountered.

Percoraro et al. (7) evaluated the response to MMF in 12 children with SDNS (mean age 10.9 yr). Each patient underwent a renal biopsy, which showed FSGS in two and minimal change NS in 10. MMF was given at a dosage of 27.8 mg/kg per d for a period of 24 mo after NS remission was induced with steroids. The features of these patients were comparable to those reported in our study, and the children enjoyed a similar good response, with 82% staying in remission while on MMF.

It is evident from the reports summarized herein that the use of MMF in children with FRNS and/or SDNS has met with success of varying degrees. The encouraging results that have been obtained by many of the investigators certainly provide an optimistic framework for the development of controlled clinical trials to define better the efficacy and the safety of this agent in the conditions described. The results observed in our patients confirm and extend the previous observations. At this time, it seems reasonable to conclude that MMF is a viable option for pediatric nephrologists to consider as therapy for children with FRNS. However, it must be emphasized that final conclusions regarding the use of this agent in children with FRNS must await the results from adequately powered, controlled studies, as discussed recently by Moudgil et al. (20).


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  		Appendix: Participating centers, principal investigators, and study coordinators

 

   Acknowledgments
 
This study was supported by an investigator-initiated grant from Roche Laboratories, and the MMF that was used in the trial was donated by Roche Laboratories.


   Footnotes
 
Published online ahead of print. Publication date available at www.cjasn.org.

Received February 14, 2006. Accepted August 25, 2006.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Bartosh SM: The use of mycophenolate mofetil in children with nephrotic syndrome [Abstract]. J Am Soc Nephrol10 :95A ,1999
  2. Barletta G, Smoyer W, Bunchman T, Flynn J, Kershaw D: Use of mycophenolate mofetil in steroid-dependent and -resistant nephrotic syndrome. Pediatr Nephrol18 :833 –837,2003[CrossRef][Medline]
  3. Bagga A, Hari P, Moudgil A, Jordan S: Mycophenolate mofetil and prednisolone therapy in children with steroid-dependent nephrotic syndrome. Am J Kidney Dis42 :1114 –1120,2003[CrossRef][Medline]
  4. Gellerman J, Querfeld U: Frequently relapsing nephrotic syndrome: Treatment with mycophenolate mofetil. Pediatr Nephrol19 :101 –104,2004[CrossRef][Medline]
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  6. Ulinski T, Dubourg L, Said M, Parchoux B, Ranchin B, Cochat P: Switch from cyclosporine a to mycophenolate mofetil in nephrotic children. Pediatr Nephrol20 :482 –485,2005[CrossRef][Medline]
  7. Pecoraro C, Ferretti A, Malgieri G, Mirella G, D’Armiento M, Bisesti V, Caropreso M: Two years mycophenolate mofetil treatment of childhood steroid dependent and cyclosporin a dependent nephrotic syndrome [Abstract]. J Am Soc Nephrol16 :557A ,2005
  8. Chandra M, Susin M, Abitbol C: Remission of relapsing childhood nephrotic syndrome with mycophenolate mofetil. Pediatr Nephrol14 :224 –226,2000[CrossRef][Medline]
  9. Choi MJ, Eustace JA, Gimenez LF, Atta MF, Scheel PJ, Sothinathan R, Briggs WA: Mycophenolate mofetil treatment for primary glomerular diseases. Kidney Int61 :1098 –1114,2002[CrossRef][Medline]
  10. Pesavento T, Bay W, Agarwal G, Hernandez RA Jr, Hebert L: Mycophenolate therapy in frequently relapsing minimal change disease that has failed cyclophosphamide therapy. Am J Kidney Dis43 :E10 ,2004[Medline]
  11. Day CJ, Cockwell P, Lipkin GW, Savage CO, Howie AJ, Adu D: Mycophenolate mofetil in the treatment of resistant idiopathic nephrotic syndrome. Nephrol Dial Transplant17 :2011 –2013,2002[Abstract/Free Full Text]
  12. Hamasaki T, Mori M, Kinoshita M, Saeki T, Sakano T: Mizoribine in steroid-dependent nephrotic syndrome of childhood. Pediatr Nephrol11 :625 –627,1997[CrossRef][Medline]
  13. Yoshioka K, Ohashi O, Sakai T, Ito H, Yoshikawa N, Nakamura H, Tanizawa T, Wada H, Maki S; for the Pediatric Mizoribine Study Group in Japan: A multicenter trial of mizoribine compared with placebo in children with frequently relapsing nephrotic syndrome. Kidney Int58 :317 –324,2000[CrossRef][Medline]
  14. Kawasaki Y, Hosoya M, Kobayashi S, Ohara S, Onishi N, Takahashi A, Isome M, Suzuki H: Oral mizoribine pulse therapy for patients with steroid-resistant and frequently relapsing steroid-dependent nephrotic syndrome. Nephrol Dial Transplant20 :2243 –2247,2005[Abstract/Free Full Text]
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  17. Honda M: Nephrotic syndrome and mizoribine in children. Pediatr Int44 :210 –216,2002[CrossRef][Medline]
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  19. Schwartz GJ, Haycock GB, Edelmann CH Jr, Spitzer A: A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics58 :259 –263,1976[Abstract/Free Full Text]
  20. Moudgil A, Bagga A, Jordan SC: Mycophenolate mofetil therapy in frequently relapsing steroid-dependent and steroid-resistant nephrotic syndrome of childhood: Current status and future directions. Pediatr Nephrol20 :1376 –1381,2005[CrossRef][Medline]




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