Pediatric Nephrology

, Volume 23, Issue 10, pp 1877–1882

Maintenance therapy with mycophenolate mofetil for children with severe lupus nephritis after low-dose intravenous cyclophosphamide regimen

Authors

    • Division of NephrologySaitama Children’s Medical Center
  • Yoshiyuki Ohtomo
    • Department of PediatricsJuntendo Nerima Hospital
  • Satoshi Hara
    • Division of NephrologySaitama Children’s Medical Center
  • Daisuke Umino
    • Department of PediatricsJuntendo University School of Medicine
  • Tomonosuke Someya
    • Department of PediatricsJuntendo University School of Medicine
  • Toshiaki Shimizu
    • Department of PediatricsJuntendo University School of Medicine
  • Kazunari Kaneko
    • Department of PediatricsKansai Medical University
Brief Report

DOI: 10.1007/s00467-008-0800-7

Cite this article as:
Fujinaga, S., Ohtomo, Y., Hara, S. et al. Pediatr Nephrol (2008) 23: 1877. doi:10.1007/s00467-008-0800-7

Abstract

Although recent studies on adults with lupus nephritis indicate that mycophenolate mofetil (MMF) may be effective in maintaining remission for patients who previously received short-term intravenous cyclophosphamide (IVCY) induction therapy, the experience with the new immunosuppressive agent in children with severe lupus nephritis has not been as satisfactory thus far. To assess the efficacy and safety of maintenance therapy with MMF, we prospectively analyzed four patients with biopsy-proven severe lupus nephritis (three girls, one boy; mean age 12 years; two with class IIIA, two with class IVG(A); mean duration of lupus nephritis 7 months) receiving MMF for at least 6 months after induction treatment. These patients had been treated previously with 6 months of low-dose IVCY combined with oral mizoribine and steroids for induction, followed by therapy with MMF adjusted to maintain predose mycophenolic acid (C0-MPA) levels at 2–5 mcg/ml. Mean follow-up after staring MMF was 27.5 months (range 6–41). The mean MMF dose required was 405 ± 49 mg/m2 per 12 h, which maintained mean C0-MPA levels of 3.3 ± 0.41 mcg/ml. No patient experienced renal flares during maintenance therapy with MMF, which permitted a significant reduction in mean prednisolone dose from 11.9 ± 1.3 to 3.9 ± 2.6 mg/day (P = 0.003). No significant gastrointestinal or hematologic side effects of MMF were noted. This preliminary study demonstrates that maintenance therapy with MMF after a low-dose IVCY regimen appears to be a promising intervention without adverse effects in children with severe lupus nephritis. These data should be confirmed by a prospective randomized multicenter clinical trial.

Keywords

Maintenance therapyMycophenolate mofetilLupus nephritisIntravenous cyclophosphamide

Introduction

Clinical symptoms of systemic lupus erythematosus (SLE) are often more severe in children than in adults. Renal involvement develops in 30–70% of children with SLE [1], and the risk of progression to end-stage renal disease (ESRD) in childhood lupus nephritis is 18–50% [2]. The optimal induction therapy is crucial because recent data from the Euro-Lupus trial show that the early response to therapy at 6 months was the best predictor of good long-term renal outcome [3]. We previously reported in this journal the efficacy and safety of a 6-month induction therapy of low-dose intravenous cyclophosphamide (IVCY), oral mizoribine, and steroids for children with severe lupus nephritis [4]. Our patients responded well to this regimen, showing remarkable improvement in both histological and clinical manifestation in a short of period time. Flare, however, is the strongest predictor of progression to ESRD once remission is achieved. Therefore, once proteinuria and serum creatinine are controlled with short-term induction therapy, the aim shifts to preventing flares [5].

Mycophenolate mofetil (MMF), an immunosuppressive agent that inhibits both B- and T-cell proliferation, is used primarily for rejection prophylaxis in renal transplant recipients. Because of its potent immunosuppressive action, MMF has emerged as a new agent for treating patients with glomerular disease, including lupus nephritis, without serious adverse effects such as gonadal toxicity [6, 7]. Recently, a randomized controlled trial for adult patients with lupus nephritis in whom remission had been induced with short-term IVCY demonstrated that relapse-free survival was higher in patients treated with MMF compared with long-term IVCY regimen. In addition, the incidence of hospitalization, amenorrhea, infections, nausea, and vomiting was significantly lower in the MMF group than in the IVCY group [8]. However, there is no consensus on the best way to monitor its efficacy and tailor its dose because of the lack of data, especially in children with lupus nephritis. Borrows et al. recently reported that trough levels of mycophenolic acid (MPA), the active metabolite of MMF, were associated with acute rejection and toxicity in renal transplant recipients [9].

In this study, we examined the efficacy and safety of maintenance therapy with MMF by predose MPA-level monitoring in children with severe lupus nephritis after induction therapy.

Patients and methods

Four children (three girls, one boy) who fulfilled the classification criteria for SLE at Saitama Children’s Medical Center from January 2004 to November 2006 were enrolled into the study [10] and followed for a mean of 34.5 months (range 14–47). All patients were considered to have severe lupus nephritis, as renal insufficiency and histologically proliferative glomerulonephritis [the 2003 International Society of Nephrology/Renal Pathology Society (ISN/RPS) class III or IV] were present at disease onset [11].

Induction therapy for children with severe lupus nephritis at our center consisted of low-dose IVCY combined with oral mizoribine and steroids [4]. Subsequently, patients were treated with MMF and a tapering dose of PSL for remission maintenance after a second renal biopsy had been performed to assess induction therapy efficacy. MMF (Cellcept, oral formulation, Chugai Co., Tokyo, Japan) was commenced at an initial dose of 250 mg/12 h, adjusted to maintain stable C0-MPA levels at 2–5 mcg/ml unless white blood cell counts fell below 3,000/μl. The MPA was measured every 1–3 months in plasma by the Special Reference Laboratory (SRL), Inc. using the enzyme-mediated immunotechnique (EMIT). Concomitant oral prednisolone (PSL) dosages were tapered by 10–20% at more than 4-week intervals on the basis of clinical laboratory improvement.

The end points of the study were renal flare as defined by an increase in urinary protein:creatinine ratio to more than 1.0 (proteinuric) or by an increase in the serum creatinine level of 50% for more than 1 month (nephritic); hospitalization, bacterial infection, and other adverse events. Remission was defined as a decrease in urinary protein:creatinine ratio to less than 0.2, accompanied by improved renal function.

All patients and their parents gave informed consent, and the study was approved by the Institutional Ethics Board.

To assess treatment outcome and detect potential drug toxicity, clinical and laboratory assessments were performed 2 weeks after initiation of MMF therapy and then at monthly intervals. Laboratory assessments included urinalysis, complete blood counts, serum creatinine, blood urea nitrogen, electrolytes, transaminases, bilirubin, amylase, uric acid, antinuclear antibodies, anti-double-stranded DNA (anti-dsDNA) antibodies and complement fractions C3-C4.

Data are reported as mean ± standard deviation (SD). Numerical data were analyzed using paired t test (two-tailed), and the level of statistical significance was set at P < 0.05.

Results

The characteristics of four patients at disease onset and at start of MMF therapy are shown in Table 1. The patients were diagnosed with SLE at an average of 11.5 years (range 8.7–12.6). Renal biopsy was performed in all patients at disease onset: histological diagnoses were class IIIA in two and class IVG(A) in two. Patients had been previously treated with a low-dose IVCY regimen for remission induction and subsequently were switched to maintenance therapy with MMF at an average age of 12 years (range 9.3–13). Three of four patients were hypertensive at disease onset. Hypertension was treated with angiotensin II receptor blockers in three and calcium channel blockers in one patient in the induction therapy. Proteinuria had already disappeared and renal function had recovered in all patients during the induction therapy. Furthermore, second renal biopsies after induction therapy revealed that active lesions had almost disappeared. However, anti-dsDNA antibody increased above normal levels in two children, and serum C3 and C4 decreased below normal levels in three and four children, respectively.
Table 1

Clinical characteristics of four patients at disease onset/at start of mycophenolate mofetil (MMF)

No.

Age (years)

Histological findings (ISN/RPS)

Proportion of glomeruli affected by active lesions (%)

Urinary protein: creatinine ratioa

Serum creatinine (mg/dl)

C3 (mg/dl)

C4 (mg/dl)

Anti-dsDNA antibody (IU/ml)

1

12.1/12.6

IVG(A)/IIIC

100/0

2.7/0.18

0.84/0.57

31/83

<5/15

400</31

2

12.5/13

IIIA/II

22/0

1.0/0.05

0.93/0.65

22/83

<5/12

34.6/4.8

3

8.7/9.3

IIIA/IIIC

42/0

2.3/0.08

1.15/0.63

<16/104

<5/8

400</30

4

12.6/13.3

IVG(A)/IIIAC

100/9

3.2/0.06

0.67/0.47

21/77

1/12

400</19.7

ISN/RPS International Society of Nephrology/Renal Pathology Society, dsDNA double-stranded DNA

aSecond morning urine specimen

Mean flow-up period after starting MMF was 27.5 months (range 6–41). The mean MMF dose required was 405 ± 49 mg/m2 per 12 h (434, 452, 341, 341 mg/m2 per 12 h, respectively), which maintained mean C0-MPA levels of 3.3 ± 0.41 mcg/ml (3.4, 2.9, 3.9, 3.2 mcg/ml, respectively). Therapy with MMF resulted in steroid sparing without a renal flare during a follow-up period. The mean dose of PSL used in combination with MMF was significantly reduced from 11.9 ± 1.3 mg/day at the beginning to 3.9 ± 2.6 mg/day (P = 0.003) at the end of follow-up (Fig. 1). Furthermore, anti-dsDNA antibody and serum complement levels improved in all patients (Figs. 2, 3 and 4).
https://static-content.springer.com/image/art%3A10.1007%2Fs00467-008-0800-7/MediaObjects/467_2008_800_Fig1_HTML.gif
Fig. 1

Prednisolone dose (mg/day) in patients (1–4) after the initiation of mycophenolate mofetil (MMF) therapy

https://static-content.springer.com/image/art%3A10.1007%2Fs00467-008-0800-7/MediaObjects/467_2008_800_Fig2_HTML.gif
Fig. 2

Serum C3 (mg/dl, normal 85–160) levels in patients 1–4 after the initiation of mycophenolate mofetil (MMF) therapy

https://static-content.springer.com/image/art%3A10.1007%2Fs00467-008-0800-7/MediaObjects/467_2008_800_Fig3_HTML.gif
Fig. 3

Serum C4 (mg/dl, normal 16–45) levels in patients 1–4 after the initiation of mycophenolate mofetil (MMF) therapy

https://static-content.springer.com/image/art%3A10.1007%2Fs00467-008-0800-7/MediaObjects/467_2008_800_Fig4_HTML.gif
Fig. 4

Anti-double-stranded DNA antibody (IU/ml, normal <20) in patients 1–4 after the initiation of mycophenolate mofetil (MMF) therapy

No significant hematological side effects of MMF, such as leukopenia (<3,000/mm3), erythropenia (<350 × 104/mm3), thrombocytopenia (<15 × 104/mm3), or liver dysfunction, were noted. No patient experienced gastrointestinal side effects, including nausea and diarrhea, or bacterial infection during MMF therapy.

Discussion

IVCY had been the standard of care for severe and proliferative lupus nephritis for more than 20 years based on randomized trials carried out at the National Institutes of Health [12, 13]. Although patients receiving long-term IVCY had a significantly greater likelihood of lack of renal flare than those receiving shorter protocols, this prolonged IVCY regimen has considerable toxicity, including increased risk of bacterial infections, hemorrhagic cystitis, malignancies, and gonadal toxicity. Furthermore, recent studies demonstrate that time to response averages 10.5 months, and many patients fail to achieve remission and relapses occur despite maintenance therapy with IVCY [14, 15]. To obtain remission earlier with optimal induction therapy is critical, because Houssiau et al. demonstrated by multivariate analysis that early response to therapy at 6 months (defined as a decrease in serum creatinine level and proteinuria <1 g/day) was the best predictor of good long-term renal outcome in the Euro-Lupus Nephritis Trial [3]. All our patients responded well within 6 months to the induction therapy with low-dose IVCY in combination with oral mizoribine and steroids. Thus, we believe that the new low-dose IVCY regimen may represent a valuable alternative to the traditional induction protocol for children with severe lupus nephritis and may lead to the reduction in steroid dose in the maintenance treatment of lupus nephritis, although the efficacy of this regimen should be confirmed by a large-sample randomized controlled trial.

Although maintenance therapy should aim at reducing the risk of drug toxicity, prevention of flare, which is regarded as a risk factor for the development of ESRD, is also important. In fact, Moroni et al. reported that patients who had nephritic flares were almost seven times as likely to progress to ESRD than those who did not experience flares [15]. Recently, Contreras et al. compared long-term IVCY with MMF or azathioprine (AZA) in 59 patients in whom remission had been induced with short-term IVCY [8]. They found that relapse-free survival was higher in patients treated with MMF compared with those receiving IVCY (P = 0.02). Additionally, the incidence of hospitalization and adverse effects such as amenorrhea were significantly lower in the MMF and AZA groups than in the IVCY group. Therefore, MMF and AZA may have a role as remission-maintenance therapy for adult patients, but in children with lupus nephritis, experience with immunosuppressive agents is very limited [1619]. At present, no controlled studies comparing MMF with AZA exist for children. Hagelberg et al. suggested a satisfactory response to long-term AZA in a retrospective review for children with lupus nephritis [16]. However, the non-Caucasian children in their study had only a 56% long-term survival. The beneficial effect they ascribe to AZA may only be applicable to Caucasian patients. The use of AZA for childhood lupus nephritis has been largely abandoned in favor of newer, more effective, therapies [20]. Buratti et al. reported the first clinical experience in 11 children treated with MMF (22 mg/kg per day) for various forms of refractory lupus nephritis over a mean of 9.8 months (range 3–17) [17]. This study saw a greater improvement in renal function in those patients with membranous glomerulonephritis than in those with proliferative glomerulonephritis. In addition, eight of 11 (73%) children experienced adverse effects such as infection and leucopenia. In contrast, therapy with MMF resulted in marked steroid sparing without flare and adverse events during follow-up in our patients with proliferative glomerulonephritis. In terms of such differences, previous cytotoxic therapy and disease duration before MMF in Buratti’s group were various compared with our homogeneous patient group. Furthermore, MMF dosage was increased stepwise to ascertain the safety of the drug, and we regularly monitored C0-MPA levels in our all patients, which may have prevented adverse events and improved treatment compliance.

With regard to mode of action, MPA, the active metabolite of MMF, is a selective reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH) that inhibits de novo synthesis of purines [21]. Lymphocytes differ from other cells in that they are not able to use the salvage pathways to synthesize purines. MMF therefore exerts cytostatic effect specifically on lymphocytes. MMF has been used extensively for treating renal transplant rejection. When compared with AZA-treated transplant patients, those treated with MMF had decreased antibody levels following immunization, suggesting a role for MMF in autoimmune antibody-mediated disease such as SLE. The question remains, however, as to the optimal dose of the treatment with MMF in pediatric lupus nephritis. To this end, it is still unknown whether there is any pharmacokinetics variability with age and race [18]. A 50% inhibition of IMPDH, proposed to be sufficient for immunosuppression, was found at the area under the curve (AUC) of 59 mcg × h/ml and MPA trough concentrations of between 2 and 5 mcg/ml [22]. We therefore use these as target ranges in our patients. The mean dosage of MMF (405 mg/m2 per 12 h) was approximately two thirds of the current recommended dosage for pediatric renal transplant recipients (600 mg/m2 per 12 h).

In summary, this preliminary study demonstrates that maintenance therapy with MMF by monitoring C0-MPA levels appears to be a promising intervention without adverse effects in children with severe lupus nephritis after a low-dose IVCY regimen. However, larger randomized controlled studies are needed to confirm this, and it must be kept in mind that the use of MMF is still considered off label.

Copyright information

© IPNA 2008