Pediatric Nephrology

https://doi.org/10.1007/s00467-018-3970-y

EDUCATIONAL REVIEW

Mycophenolate mofetil for sustained remission in nephrotic syndrome

Uwe Querfeld 1 & Lutz T. Weber 2

Received: 23 November 2017 / Revised: 13 April 2018 / Accepted: 17 April 2018

# IPNA 2018

Abstract
The clinical application of mycophenolate mofetil (MMF) has significantly widened beyond the prophylaxis of acute and chronic
rejections in solid organ transplantation. MMF has been recognized as an excellent treatment option in many immunologic
glomerulopathies. For children with frequently relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome
(SDNS) experiencing steroid toxicity, MMF has been recommended as a steroid-sparing drug. Uncontrolled studies in patients
with FRNS and SDSN have shown that many patients can achieve sustained remission of proteinuria with MMF monotherapy.
Three randomized controlled trials have similarly demonstrated that MMF is beneficial in these patients, but less effective than
the calcineurin inhibitors cyclosporin A or tacrolimus. Some, but not all, patients with steroid-resistant nephrotic syndrome
(SRNS) may also respond to MMF, usually given in combination with other drugs, with partial or complete remission. There are
important limitations to the interpretation and comparability of these studies including study design, sample size, patient selec-
tion, clinical endpoints, carry-over effects, and duration of follow-up. In all studies, MMF had relatively few side effects, no
nephrotoxicity, or no systemic toxicity. MMF is teratogenic, and contraceptive advice is required in females. There is a poor
correlation between MMF dose and mycophenolic acid (MPA) exposure and significant inter- and intra-patient variability in drug
pharmacokinetics. A higher estimated MPA-AUC0–12 target range than recommended for pediatric renal transplant recipients is
essential to prevent relapses. Therefore, therapy should be guided by drug monitoring to avoid relapses. Further studies are
needed to test the efficacy of MMF in inducing remission and, as part of a combination therapy, achieving sustained remission in
patients with SRNS.

Keywords Idiopathic nephrotic syndrome . Corticosteroids . Mycophenolate mofetil . Mycophenolic acid . Cyclosporin A .
Tacrolimus

Introduction accompanied by severe adverse effects, including, but not

Idiopathic nephrotic syndrome (INS) is the most frequent glo-
merular disease in children. About 85% of affected patients
have minimal change nephrotic syndrome (MCNS), which is
most often sensitive to treatment with corticosteroids (steroid-
sensitive nephrotic syndrome (SSNS)), with relapses occur-
ring in 80–90% [1]. About 50% of patients with relapses have
frequently relapsing nephrotic syndrome (FRNS), and of
these, 30–50% steroid-dependent nephrotic syndrome
(SDNS). Prolonged use of corticosteroids is often
* Uwe Querfeld
Uwe.querfeld@charite.de
1
Pediatric Nephrology, Charité Campus Virchow,
13353 Berlin, Germany
2
University Children’s Hospital, Cologne, Germany
limited to, the development of obesity, diabetes, arterial hy-
pertension, bone demineralization, aseptic bone necrosis, di-
minished growth, cataracts, infectious complications, and
thrombotic complications.
Therefore, non-steroid immunosuppressive agents have
been empirically used for treatment of children with FRNS,
SDNS, and SRNS (recently reviewed by the Cochrane group)
[2] and their use has been recommended for patients
experiencing steroid-related adverse effects by the expert
KDIGO work group [3] and by an expert group of the
German Society for Pediatric Nephrology (GPN) [4]. The
published data of clinical trials of steroid-sparing agents indi-
cate that alkylating agents (cyclophosphamide, chlorambucil),
calcineurin inhibitors (cyclosporine, tacrolimus), levamisole,
rituximab, and mycophenolate mofetil induce or preserve re-
mission in FRNS and SDNS and might be considered as
steroid-sparing agents, whereas azathioprine and mizoribine
have no significant therapeutic effect. Unfortunately,

therapeutic use of all of these agents has been associated with
distinct side effects, and there is currently no consensus on the
choice of a first-line steroid-sparing agent for patients with
FRNS or SSNS [5].
We here review the experience with MMF in children with
the idiopathic nephrotic syndrome.
Mycophenolate mofetil
Immune actions
Mycophenolate mofetil (MMF) is an ester prodrug of the im-
munosuppressant mycophenolic acid (MPA) and is widely
used for maintenance immunosuppressive therapy in pediatric
renal transplant recipients. MPA acts as a potent, reversible,
uncompetitive inhibitor of inosine monophosphate dehydro-
genase (IMPDH), the key enzyme in the de novo purine bio-
synthesis in proliferating T and B lymphocytes, thereby sup-
pressing cell-mediated immune responses and antibody for-
mation. In addition, MPA inhibits adhesion molecule glyco-
sylation and expression as well as lymphocyte and monocyte
recruitment [6]. MPA also induces apoptosis of immune cells.
Proliferating T and B cells are preferentially dependent on
the de novo purine synthesis. This is why MPA has a quite
specific effect on proliferating lymphocytes. In contrast, other
cells (e.g., brain cells) exclusively utilize the so-called salvage
pathway that is based on recycling of purine bases [7]. In the
majority of eukaryotic cells, purine synthesis can be achieved
by both pathways.
Non-immune actions
The clinical application of MMF has significantly widened
beyond the prophylaxis of acute and chronic rejections in solid
organ transplantation. For example, it has become part of the
first-line therapy in lupus nephritis [8, 9] and meanwhile has
been recognized as an excellent treatment option in many
immunologic glomerulopathies, firstly, because MPA pos-
sesses the immunosuppressive properties described above.
Moreover, MPA has a remarkable effect also on non-
immune cells and counteracts the proliferation of mesangial
cells, the expansion of mesangial matrix, and the foot process
effacement of podocytes [10–14].
Similar to lymphocytes, mesangial cells are partially de-
pendent on de novo purine biosynthesis and thus susceptible
for MPA treatment. Additionally, MPA can inhibit apoptosis
in podocytes and seems to be beneficial in preserving the
expression of nephrin and podocin; by attenuation of uroki-
nase receptor expression, MPA leads to decreased foot process
effacement [15]. Thereby, MPA seems to exert a direct
antiproteinuric effect that makes it a valuable drug in the treat-
ment of nephrotic syndrome.
Pediatr Nephrol
Potential toxicities
MMF has low systemic toxicity, and only few side effects
have been reported in nephrotic patients. However, in combi-
nation with other immunosuppressants, MMF may have more
serious side effects, especially infections. In transplanted pa-
tients, multifocal leukoencephalopathy has been linked to
MMF therapy [16, 17]. Of note, MMF has teratogenic poten-
tial and in utero exposure has been associated with a specific
embryopathy; women should be counseled on the risk of this
drug, and for women considering pregnancy, it is recommend-
ed to stop treatment with MMF at least 6 weeks before be-
coming pregnant [18].
Principal limitations of clinical trials in patient
with relapsing NS
There are several important limitations which need to be con-
sidered in the interpretation of results of clinical trials.
& The INS may follow its natural course and resolve with
time. Treatment effects may thus be falsely attributed to a
particular medication.
& The disease affects mainly boys, and results of all studies
may be biased by a preponderance of male participants;
drug effects could be different in girls.
& The response to steroids may be variable, even within
histological categories on renal biopsy. Thus, and for rea-
sons unknown, patients with MCNS may be steroid resis-
tant or become steroid resistant, and patients with FSGS
may be steroid responsive and may become steroid resis-
tant. It is unknown to what extent patients with primary or
late steroid resistance, even with MCNS, will respond to
other immunosuppressive drugs. Thus, inclusion of these
patients in clinical studies may be problematic.
& All steroid-sparing drugs used for treatment of the NS
have strong immunosuppressive properties. Very little is
known about interactions of these immunosuppressants
when given in combination or in sequence [19].
However, drug effects may last for unknown periods of
time, by far exceeding the time of medication intake.
Thus, a single dose of rituximab may lead to a significant
depletion of memory B cell subsets measured after 1 year
[20]. Typically, patients with unremitting FRNS or SDNS
receive multiple courses of different steroid-sparing agents
within a few years; if such patients are enrolled into clin-
ical studies, their drug history may be a major factor de-
termining response to treatment. As an example, in the
crossover trial conducted by the GPN, the efficacy of
MMF was significantly different when the patients re-
ceived the drug in the first year of the study or in the
second year after switching from cyclosporin A (CsA) to
Pediatr Nephrol
MMF. There were significantly more relapses per patient
per year with MMF compared to CsA therapy during the
first year (1.10 vs. 0.24; p = 0.034), but not during the
second year (0.40 vs. 0.20; p = 0.14). It is currently un-
known to what extent and how long such carry-over ef-
fects may affect treatment results.
& Finally, drug pharmacokinetics may show large inter- and
intra-individual variability and study results may differ,
depending on the use of therapeutic drug monitoring
(TDM). Unfortunately, TDM has not been standardized
and different algorithms are used to estimate MPA-AUC.
Preferably, blood samples should be analyzed within
hours and results reported on the same day. Differences
in local TDM methodology and logistics may therefore
impact results of clinical studies, especially in multicenter
trials.
Randomized clinical trials
There have been only a few randomized clinical trials (RCTs)
in children with either frequently relapsing or steroid-
dependent SSNS (Table 1). Dorresteijn et al. enrolled 24 chil-
dren for 12 months and observed a higher relapse rate in
patients treated with MMF than with CsA (p = 0.08) after
12 months of treatment [21]. While this study was underpow-
ered as acknowledged by the authors, the RCT conducted by
the German Society for Pediatric Nephrology, which enrolled
60 patients, confirmed the higher efficacy of CsA [22]. In this
crossover study, with an adequate sample size based on a non-
inferiority power calculation, every patient received either
MMF or CsA for 12 months, followed by treatment with the
other drug for a second year. No relapses occurred in 85% of
patients during CsA therapy and in 64% of patients during
MMF therapy (p = 0.06). Probably due to carry-over effects
of the more potent medication with CsA, more relapses per
patient per year occurred with MMF than with CsA during the
first year (p = 0.03), but not during the second year (p = 0.14).
Similarly, the time without relapse was significantly longer
with CsA than with MMF during the first year (p < 0.05),
but not during the second year (p = 0.36).
Importantly, treatment with both medications was adjusted
by pharmacokinetic monitoring every 6 months. The MMF
starting dose was 1000 mg/m2/day in two doses and the target
plasma MPA trough level 1.5–2.5 μg/ml, while CsA was giv-
en at a dose of 150 mg/m2 in two doses with a target trough
level of 80–100 ng/ml. A post hoc analysis revealed that pa-
tients with low mycophenolic acid exposure (AUC < 50 μg·h/
ml) experienced 1.4 relapses per year compared with 0.27
relapses per year in those with high exposure (AUC >
50 μg·h/ml; p < 0.05). The relapse-free time was significantly
higher in patients with a high MMF exposure compared to
those with a low exposure (p = 0.03) and not different com-
pared to patients treated with CsA (p = 0.32).
Sinha and colleagues performed an RCT comparing MMF
treatment with tacrolimus (TAC) in children with steroid-
resistant nephrotic syndrome (early or late steroid resistance
with minimal changes or focal segmental sclerosis on biopsy)
achieving remission for 6 months with Tac, prednisolone, ac-
companied by enalapril and calcium carbonate medication
[23]. During remission, patients were randomized to receive
MMF or continue with Tac for 12 months. The proportion of
patients with a favorable outcome (sustained remission, infre-
quent relapses) at 1 year was significantly lower (44.8%) in
the MMF group than in the Tac group (90.3%). The authors
concluded that replacing tacrolimus with MMF after 6 months
of tacrolimus therapy for SRNS is associated with significant
risk of frequent relapses or recurrence of resistance.
In these controlled studies, MMF was generally well toler-
ated. All RCTs reported mostly minor side effects, although
there was a higher tendency for serious adverse effects in the
MMF group in the study by Sinha et al. Interestingly, hemo-
globin levels were significantly lower in patients treated with
CSA compared to MMF in both CsA studies, and there was a
higher incidence of anemia in patients treated with Tac than
with MMF. Altogether, the calcineurin inhibitors CsA and Tac
performed better than MMF in all randomized trials.
Uncontrolled studies evaluating MMF
monotherapy in FRNS or SDNS
In these hospital-based cohort studies (Table 2), MMF was
introduced as a steroid-sparing agent. In most studies, patients
had been previously treated with other immunosuppressants.
The clinical endpoints in these studies were different, making
them hardly comparable. Further issues limiting the relevance
of these data for clinical decision making are the small number
of subjects involved, lack of randomization, and only a short
follow-up period in most studies. However, MMF was bene-
ficial in all studies, associated with a higher remission/lower
relapse rate or lower steroid requirements if compared to a
previous treatment period with corticosteroids or in patients
switched from CsA. MMF was equally [33] or less [35] effi-
cacious compared to Tac treatment in two uncontrolled trials.
Only few MMF-related side effects were reported in all of
these studies.
Uncontrolled studies including SRNS patients
evaluating MMF monotherapy
Several pediatric centers have published their experience with
MMF treatment in cohorts including patients with SSNS and
SRNS (Table 3).
 Pediatr Nephrol

Table 1 MMF treatment of nephrotic syndrome in childhood: randomized clinical trials

Author/year/country Comparator Primary endpoint Type of study N (age) Dose per day Outcome
[ref.] (clinical Histological
classification) classification

Dorresteijn MMF or CsA for Number of Prospective 24 MMF 1200 mg/m2 Relapse rate in the
et al./2008/Holla- 12 months relapses open label (3.7–- (n = 12) or CsA MMF group
nd [21] (8 FRNS, 17.5 years) 4–5 mg/kg (n = 12) 0.83/year vs.
16 SDNS) All patients for 12 months 0.08/year in the CsA
SSNS, group (p = 0.08)
MCNS
Gellermann MMF vs. CsA, each Number of Prospective, 60 (3.3–17.0 y)MMF 1000 mg/m2 No relapses in 85% of
et al./2013/Germ- drug for 12 months, relapses open label, All patients starting dose; target patients during CsA
any [22] then crossover 24 month- SSNS, plasma MPA trough therapy and in 64%
s, MCNS level 1.5–2.5 μg/ml) of patients during
crossover or CsA 150 mg/m2 MMF therapy
at in 2 doses (target (p = 0.06). More
12 months trough level relapses per patient
(14 FRNS, 80–100 ng/ml) per year with MMF
46 SDNS) than with CsA
during the first year
(p = 0.03), but not
during the second
year (p = 0.14)
Sinha MMF or Tac for Proportion of Prospective, 60 (2–6.6 years) Tac 0.1 to 0.15 mg/kg Better outcome with
et al./2017/India 12 months, patients with open label 56.7% or MMF tacrolimus (90.3%)
[23] maintaining complete or for MCNS, 750–1000 mg/m2 vs. MMF (44.8%)
remission of partial 12 months 43.3% FSGS Prednisolone (p = 0.0002)
proteinuria; SRNS in remission with (60 SRNS) tapered to a dose of
complete or partial or without (46.7% 0.2 to 0.3 mg/kg
remission after infrequent had initial q.o.d. for 12 months
6 months of therapy steroid-- steroid in both groups.
with tacrolimus sensitive resistance)
relapses

CsA cyclosporine A, q.o.d. every other day, Tac, tacrolimus, y years, MMF mycophenolate mofetil, SDNS steroid-dependent nephrotic syndrome, SRNS
steroid-resistant nephrotic syndrome, FRNS frequently relapsing nephrotic syndrome, MCNS minimal change nephrotic syndrome

Studies describing MMF use in other glomerulopathies or
with incomplete description of medication data or available
only in abstract form [44–46] have not been included in these
tables. MMF was beneficial and had a steroid-sparing effect in
all studies, but more effective in maintaining remission in
patients with SSNS. However, a varying percentage of pa-
tients with SRNS also achieved remission with MMF mono-
therapy. Taken together, these studies (again highly varying in
their design) suggest that MMF is a valuable pharmaceutical
option in patients with SSNS and/or SRNS.
MMF in combination therapy/sequential
therapy for SRNS
In a prospective study, Fujinaga et al. compared the efficacy of
MMF (adjusted to a pre-dose MPA level of 2–5 μg/ml) and
CsA (adjusted to a 2-h post-dose level of 400–500 ng/ml) in
29 children with SDNS who had previously been maintained
on CsA treatment (for > 4 years on average) and received one
dose of rituximab. The relapse rate was higher and the relapse-
free survival time shorter in patients treated with MMF after
18 months of observation [47]. Similarly, in 24 children with
SRNS who had received 2–4 doses of rituximab, treatment
with MMF in 15 patients resulted in complete remission in
10 and partial remission in 5 patients within 12 months [35].
In 9 children with SDNS treated with rituximab, Ito et al.
found lower relapse rates in patiens receiving MMF as main-
tenance therapy than in historic controls without maintenance
[48].
Gellermann et al. reported long-term follow-up observa-
tions of 23 children with primary SRNS associated with
FSGS who achieved initial remission with MP pulse therapy
and CsA. Maintenance therapy included CsA, ACE/ARB, and
tapering of corticosteroids. In 18 patients, mycophenolate mo-
fetil (MMF) (adjusted to achieve MPA trough concentrations
> 2 μg/ml) was sequentially added, and 16 patients were con-
verted to MMF monotherapy. During a follow-up time of 7
(1.7–16.5) years, sustained remission could be achieved in all
patients [49].
In a standardized protocol, Nibikakhsh et al. treated 37
patients with primary SRNS with cyclosporine A (CyA) and
Pediatr Nephrol

Table 2 MMF treatment of steroid-sensitive nephrotic syndrome in childhood: uncontrolled studies

Author/year/ Comparator Primary Type of study N (age) Dose (per day) Main outcome
country [reference [previous endpoint (clinical Histological
number] treatment with classification) classification
steroid-sparing
agents]

Bagga MMF for Relapse rate Prospective 19 29 mg/kg/day, Decreased mean relapse rate (from
et al./2003/India 12 months single (2.6–- 12 months 6.6 to 2 episodes/year), but
[24] [CyP, LEV] center 11.2 years) treatment failure in 3 patients
(SDNS) 10 MCNS
3 FSGS
6 unknown
histology
Novak MMF for Relapse rate Retrospective 21 (2–17 years) 1200–2000 mg/m2 Reduction in relapse rate from
et al./2005/USA 1.0 ± compared single 0.80 ± 0.41 to 0.47 ± 0.43 relapses
[25] 0.5 years to steroids center per month (p < 0.02).
(0.2–- (SDNS)
2.0 years)
[None]
Hogg MMF for Remission Prospective 33 (2–15 years) 1200 mg/m2 24 patients in remission for 6 months
et al./2006/USA 6 months multicenter (75%)
[26] [Multiple] (27 FRNS; 6
SDNS)
Okada MMF for Remission Prospective 11 750 and 1000 mg/m2 Complete remission in 7, fewer
et al./2007/Japa- 12 months compared single (10–- relapses in 2, no effect in 1 patient
n [27] [CsA, to CsA center 22 years)
multiple] (conversion
from CsA)
(FRNS)
Fujinaga MMF for Relapse rate Prospective 12 (5–19 years) 610 ± 95 mg/m2/12 h, 9 patients (75%) could be weaned off
et al./2007/Japa- 12 months single adjusted to MPA CsA. The relapse rate decreased
n [28] [CsA, 7 MZR] center trough levels of from 2.7 ± 1.6 to 0.6 ± 0.9
(conversion 2.4 ± 1.1 μg/ml episodes/year. The probability of
from CsA) maintaining remission without
(SDNS) relapses on MMF therapy was
lower in patients whose average
trough MPA levels were less than
2 μg/ml (p < 0.05)
Afzal MMF for 14.3 Relapse rate Retrospective 42 26.5 mg/kg 50% or more reduction in relapse rate
et al./2007/India (6–45) after single (2.6–- in 76.2% and sustained remission
[29] months 6 months center 15.6 years) in 21.4% of patients.
[35 LEV, 37 compared (SDNS)
CyP] to past
6 months
Fujinaga MMF for 19 Relapse rate Retrospective 26 1000 mg/m2 adjusted 12-monthly relapse rates decreased
et al./2009/Japa- (7–42) single (5.8–- to trough levels of from 2.5 ± 1.4 to 0.8 ± 1.2
n [30] months center 20.5 years) > 2 μg/ml [19 episodes (p < 0.01). 15 patients
[CsA, 13 (SDNS) MCNS, 7 FSGS] weaned off CsA (58%). 12
MZR] patients had been included in
previous study [28]
Baudouin MMF for Relapse Prospective 24 600 mg/m2 for 7 days, 4 patients relapsed during the first
et al./2012/Fran- 12 months during the single (2.8–- then 1200 mg/m2 6 months and 2 at months 8 and
ce [31] [Alkylating first center 14.4 years) 11; 19 patients free of relapse
agent, 17 6 months (SDNS) during the first 6 months
LEV] of MMF
treatment
Banerjee MMF for Change in Retrospective 46 (6.57 (± 3.0) 20–30 mg/kg After 1 year of, 32 (70%) patients
et al./2013/India 12 months steroid multicenter years) had reduced steroid requirement
[32] [CyP, LEV, 4 require- (SDNS) and 20 of them were able to stop
CNI] ment steroids
Wang MMF or Tac Remission Prospective 65 MMF 20–30 mg/kg No difference in remission rates
et al./2016/Chi- for rate, single (5.3–- during the first and second
na [33] 12 months relapse center, not 6.0 years) 6-month follow-ups between the
 Pediatr Nephrol

Table 2 (continued)

Author/year/ Comparator Primary Type of study N (age) Dose (per day) Main outcome
country [reference [previous endpoint (clinical Histological
number] treatment classification
with steroid- classifica-
sparing tion)
agents]

[None] rate random- 30 MMF, 35 Tac Tac 0.05–0.15 mg/kg TAC and MMF groups (97.1 vs.
compared ized adjusted to trough 90% at month 12) and in relapse
to Tac (FRNS or levels of 5–10 μg/l rates during follow-up
SDNS)
Dehoux MMF Relapse rate Single center 96 600 mg/m2 for 7 days, 67% reduction in relapse rate, 40%
et al./2016/Fran- (minimum Compared retrospec- (4.2–- then 1200 mg/m2 reduction of the cumulative annual
ce (Dehoux treatment to previous tive 10.4 years) dose of prednisone after
et al., 2016) time steroid 1995–2012 12 months
12 months) treatment (SDNS)
[Multiple]
Jellouli MMF Relapse rate Single center 30 MMF 1200 mg/m2 The average rate of relapse 1.75/year
et al./2016/Tuni- [Multiple] compared retrospec- (3.5–- before MMF and 0.45/year during
sia [34] to previous tive 16 years) MMF therapy (p < 0.0001).
steroid (SDNS) Responding patients were younger
treatment at the onset of MMF (8.57 versus
12.83, p = 0.009)
Basu MMF or Tac or Relapse rate Single center 340 MMF 1200 mg/m2 Relapse-free survival significantly
et al./2016/India LEV For and retrospec- (1.5–- Tac 0.1–0.2 mg/kg longer with Tac compared to
[35] 18 months relapse-- tive single 13 years) adjusted to trough MMF (61.7 versus 38.5%;
[None] free center levels of 5–7 ng/ml p < 0.001) or LEV (61.7 versus
survival (FRNS, Levamisol 2.5 mg/kg 24%; p < 0.0001)
with each SDNS) (q.o.d.)
drug

CNI calcineurin inhibitor, CsA cyclosporine A, LEV levamisole, Tac tacrolimus, MZR mizoribine, CyP cyclophosphamide, SDNS steroid-dependent
nephrotic syndrome, FRNS frequently relapsing nephrotic syndrome, MMF mycophenolate mofetil

alternate day prednisolone for 6 months, resulting in complete
remission in 12 and partial remission in 2 patients. The other
23 cases were then treated with CyA (5 mg/kg/day) and MMF
(30 mg/kg/day) for 6 months. Complete remission was ob-
served in 11 cases (47.82%) and partial remission in 2 cases
(8.7%) [50].
Hibino et al. reviewed the 3-year outcome of 91 patients
with SDNS or SRNS treated with a standard protocol, which
added MMF (40 mg/kg/day) to maintenance therapy with
CsA and prednisolone and/or MP pulse therapy in patients
with continuing relapses. In patients with SRNS, they could
achieve remission rates of 100% (6/6) in MCNS and 67%
(8/12) in FSGS [51].
In a prospective study including children with steroid-
and Tac-resistant (n = 10) or TacTAC-sensitive but frequent-
ly relapsing nephrotic syndrome (n = 8), Wu et al. added
either CyP (n = 6) or MMF (n = 5) or leflunomide (LEF;
n = 7) as a third immunosuppessant in a randomized manner.
This triple therapy was effective in achieving short-term
remission and preventing long-term relapses of proteinuria
during 1-year follow-up, without a significant difference
between groups [52]. Kim et al. treated 8 children with
SRNS with a sequential therapy including corticosteroids,
Tac, and MMF with a 75% response rate [53]. Some other
studies could not be evaluated since data were only available
in abstract form.
Taken together, these studies indicate that MMF is also
useful as part of a combination/sequential therapy in select-
ed patients, especially in those with secondary steroid re-
sistance or with primary steroid resistance achieving remis-
sion. Studies reporting long-term observations [49, 51, 53]
found long-term remission rates varying between 67 and
100%. These differences could be related to differences in
patient selection or other factors including dosing, compli-
ance, genetic differences in patient cohorts, and histological
diagnosis. However, MMF seems to be a valuable treatment
option for this difficult-to-treat group of patients, typically
with FSGS, and more favorable results have been found
with longer observation periods, suggesting a beneficial
effect of long-term maintenance with MMF in patients tol-
erating this medication. Here, MMF has a place in combi-
nation with ACE/ARB, calcineurin inhibitors, and pulse
therapy with methylprednisolone to achieve remission or
minimize proteinuria; an aggressive approach seems justi-
fied to prevent or at least slow down progressive loss of
GFR.
Pediatr Nephrol

Table 3 MMF treatment of steroid-sensitive and steroid-resistant nephrotic syndrome: uncontrolled studies

Author/year/country Comparator Primary Type of study N (age) Dose per day Main outcome
[reference] [previous endpoint (clinical Histological
treatment with classification) classification
steroid-sparing
agents]

Barletta et al./2003/USA MMF for Retrospective 14 (3.4–15.2 years) The mean number of relapses
[36] 12 months Relapses/- single center 5 MCNS 800–1200 m- was reduced from 2.85
[CsA (n = 10), year (9 SDNS 5 9 IgM-N g/m2 (± 0.4) prior to MMF to
CyP] SRNS) 1.07 (± 0.3) after
12 months of MMF
treatment (p < 0.01)
Montané MMF for Change in Retrospective 9 (2–15 years) 250–500 mg/m2 Up/c was 72% below
et al./2003/USA [37] 24 months proteinuria single center 9 FSGS baseline (p < 0.01) after
[MP, CyP, CsA, (SRNS; all 6 months; 3 patients had a
Tac] on ACE or complete remission by
ARB; 6 months, six had partial
pre-treatment remission
with MP)
Gellermann and Switch from Remission Retrospective 7 (9–16 yeras) Initially All patients (6 out of 7
Querfeld/2004/Germ- CsA to single center 6 MCNS 1000 mg/m2 children switched to MMF
any [38] MMF (6 SSNS, 1 1 FSGS adjusted to and 1 patient with SRNS
MMF for SRNS) trough MPA receiving MMF in addition
15–- levels of 1.5 to to CsA) achieved
39 months 4.5 mg/ml long-term remission
[CyP, LEV; MP,
plasmaphere-
sis in 1
patient with
FSGS]
Ulinski Switch from Remission Prospective 9 (3 to 16 years) Up to All SDNS patients stayed in
et al./2005/France [39] CsA to single center 1 g/1.73 m2 remission while 2 children
MMF (7 SDNS, 2 twice daily for with SRNS had no change
SRNS) 261 ± 183 day in level of proteinuria;
GFR increased from 76 ± 5
to 119 ± 6 ml/min per
1.73 m2
Mendizabal MMF for Remission Prospective 26 (5–17 years) 1200 mg/m2 Only one patient with SRNS
et al./2005/Spain [40] 6 months single center 11 MCNS adjusted to achieved complete
[MP, CsA, (21 SDNS, 5 13 FSGS trough MPA remission. In patients with
CyP] SRNS) 1 DMP levels of SDNS, steroid sparing was
1 MGN 2.5–5 μg/ml achieved in 15 and 9
remained in remission on
MMF monotherapy. In
patients with SDNS,
average trough MPA levels
< 2.5 μg/ml were
associated with double the
risk of relapses compared
to patients with levels
> 2.5 μg/ml
De Mello MMF for Complete or Retrospective 52 (2–17 years) 500–600 mg/m2 Complete remission were
et al./2010/Brazil [41] 6 months partial single center 30 FSGS achieved in 12 (23.1%),
[34 CsA] remission (SRNS) 19 MCNS partial remission 19
3 CGN (36.5%), while 21 (40.4%)
patients had no benefit
Li et al./2010/China [42] MMF for Remission Prospective 24 (8–23 months) 25–30 mg/kg Of these patients < 2 years of
6–12 months single center 15 DMP daily age, 8 had primary SRNS,
with (8 primary 4 IgM-N 16 late steroid resistance.
stepwise SRNS, 16 2 MMF treatment resulted in
reduction of late SRNS) proliferative-- complete remission in 15,
prednisone sclerotic partial remission in 6, no
3 FSGS response in 3
 Pediatr Nephrol

Table 3 (continued)

Author/year/country Comparator Primary Type of study N (age) Dose per day Main outcome
[reference] [previous endpoint (clinical Histological
treatment classification
with steroid- classifica-
sparing tion)
agents]

Hassan et al./2013/UK MMF for Remission Retrospective 73 (7.9–13.6) 1200 mg/m2 MMF was effective in 45 of
[43] 2.1 years single center 73 (62%) patients
(0.8–- (73% SDNS, (complete remission in 36
3.2 years) 18% FRNS, (49%) for > 2 years).
2% SSNS, Partial remission (with
7% SRNS) complete steroid
withdrawal) in 2 (3%)
children for > 2 years.
Complete remission for 1
to 2 years in 7 (10%)
children

CsA cyclosporin A, CyP cyclophosphamide, DMP diffuse mesangial proliferation, GN chronic glomerulonephritis, LEV levamisole, MGN membranous
glomerulonephritis, IgM-N IgM nephropathy, MP methylprednisolone, prol-scerot proliferative and sclerotic lesions, y years, Up/c urine protein/
creatinine ratio, SSNS steroid-sensitive nephrotic syndrome, SDNS steroid-dependent nephrotic syndrome, MMF mycophenolate mofetil, FSGS focal
segmental glomerulosclerosis, FRNS frequently relapsing nephrotic syndrome

Side effects clinical trials to assess efficacy of MMF for patients in

MMF was tolerated well by most patients included in the
published studies. Side effects were highly variable and most-
ly minor; only very few patients had to discontinue medica-
tion. In the controlled trials (Table 1), the frequency of overall
side effects of MMF treatment was similar to that of treatment
with CsA or tacrolimus, respectively. Diarrhea and abdominal
pain, frequently reported in children treated with MMF after
kidney transplantation [54], were infrequently observed. In
the two largest uncontrolled single center retrospective stud-
ies, the rate of gastrointestinal symptoms was 3.1% in the
study by Basu et al. (n =340) and 11.2% (6% only mild) in
the study of Dehoux et al. (n = 74) [16, 17]. In the study by
Hassan et al., which included SRNS patients, the rate of gas-
trointestinal side effects was 9% [18].
these different diagnostic categories.
& Duration of therapy: It is currently unclear how long pa-
tients with FRNS, SDNS, or SRNS should be treated with
MMF. While the therapeutic goal is to achieve sustained
remission, defined as absence of proteinuria, there are cur-
rently no biomarkers which are predictive of remission or
relapse. Many studies have described rapid relapse of the
nephrotic syndrome after discontinuation of MMF. Since
prevention of a relapsing course is essential, treatment
should therefore be planned for several years, especially
in patients with FSGS/SRNS.
Pharmacokinetics

Pharmacokinetic therapeutic drug monitoring (TDM) in gen-

A critical view of published studies
& Quality: In general, there are important limitations to the
interpretation and comparability of published studies in-
cluding study design (mostly uncontrolled), (small) sam-
ple size, patient selection (non-randomized), clinical end-
points, carry-over effects, and duration of follow-up.
& MMF efficacy: It is not possible to determine efficacy of
MMF from the published uncontrolled studies, which are
often further limited by a mix of patients with different
diagnostic categories (SSNS, SDNS, FRNS), differences
in previous treatment regiments, and times of follow-up.
There is clearly a need for more well-designed controlled
eral has the aim to optimize individual drug treatment. One
necessary precondition is an association of the drug’s pharma-
cokinetics and its clinical efficacy and/or toxicity. TDM is also
reasonable when there is high interindividual variability of
drug concentrations, when drug-drug interactions are present,
and when compliance needs to be monitored. All these argu-
ments apply to MMF [55].
There is a poor correlation between MMF dose and MPA
exposure and significant inter- and intra-patient variability in
drug pharmacokinetics [56]. This may be explained by genetic
polymorphisms in key enzymes and drug transporters, involv-
ing uridine diphosphate glucuronosyltransferase enzymes, or-
ganic anion transport polypeptides, and multidrug resistance-
Pediatr Nephrol
associated protein 2. These genetic polymorphisms are asso-
ciated with the metabolism, efficacy, and toxicity of MPA,
thus resulting in different MPA exposures and patient out-
comes [57]. For example, multidrug-resistant protein-2,
encoded by the MRP-2 gene, is an ATP-dependent efflux
transporter. The predominant role of MRP-2 is to export or-
ganic anions and xenobiotics out of cells and into the bile,
urine, and intestinal lumen. This transporter is thus responsi-
ble for the biliary excretion of the major metabolite of MPA,
the pharmacologically inactive 7-O-MPA glucuronide
(MPAG). Subsequent enterohepatic recirculation leads to sec-
ondary increases in plasma MPA concentrations 6–12 h post-
dose, which are estimated to contribute 40% (range 10–60%)
to MPA exposure. Single nucleotide polymorphisms leading
to altered MRP-2 activity may influence this process and
therefore individually affect MPA exposure.
Importantly, exposure to MPA needs to be higher in chil-
dren with nephrotic syndrome to be efficacious than in pedi-
atric renal transplant recipients. In the latter, the usual target
MPA-AUC (area under the concentration versus time curve)
derived from 12-h pharmacokinetic profiles reflecting total
body drug exposure is 30–60 mg × h/l [58]. In the group of
children with nephrotic syndrome, however, target MPA-
AUCs of > 45–50 mg × h/l were needed to preserve remission
[49, 59–61]. These studies also showed that higher MPA ex-
posure was not associated with more side effects in children
with INS.
One obvious reason for this phenomenon doubtlessly is
that immunosuppressive therapy after solid organ transplanta-
tion in general is a combined therapy whereas in FRNS or
SDNS, MMF often is used as monotherapy. This aspect is of
some importance as far as the question of the performance of
TDM in the cohort of children with nephrotic syndrome is
concerned. AUC monitoring is laborious and costly. The value
of trough-level monitoring is challenged by poor correlation
with AUC in the transplant cohort [62], and interference with
concomitant medication, especially cyclosporine A [63]. In
children with nephrotic syndrome, however, an association
of MPA trough-level monitoring with efficacy has been dem-
onstrated with higher trough levels resulting in higher rates of
remission [28, 61]. Likewise, the use of limited sampling
strategies to calculate AUC values has been validated to pre-
dict clinical outcome [22, 61], thereby offering useful alterna-
tives to full-time pharmacokinetic monitoring. Limited sam-
pling strategies have also been used to develop Bayesian esti-
mators for TDM of MMF in children with nephrotic syndrome
[64, 65]. Bayesian estimators have the advantage of also tak-
ing other factors—apart from pure pharmacokinetic parame-
ters—into account when estimating drug exposure such as
age, gender, renal function, and serum albumin concentra-
tions. Since INS is characterized by a relapsing course with
changing biomarkers with concomitant influence on MPA
pharmacokinetics (e.g., serum albumin concentrations),
Bayesian estimators might be the tool of choice to perform
TDM in this patient population.
In summary, TDM of MMF plays an important role in
children with nephrotic syndrome since several studies have
shown that a higher estimated MPA-AUC0–12 target range (>
45–50 mg × h/l) compared to the population of pediatric renal
transplant recipients (30–60 mg × h/l) is essential to prevent
relapses. If not routinely performed, TDM should therefore be
considered for children experiencing relapses during treat-
ment with MMF monotherapy for SSNS or with MMF in
combination therapy for SRNS. As previously stated, high
intra-individual variability of the drug may result in
underdosing, drug-drug interactions may be present when
used in combination with other immunosuppressants, and
compliance may be an issue; in these situations, TDM is an
extremely valuable tool for clinical decision making.
Is MMF useful in inducing remission?
So far MMF has been used for maintenance therapy, either in
patients with FSNS or in patients with SDNS in remission
after a course of corticosteroids, or as a steroid-sparing agent
in patients with ongoing SDNS or SRNS achieving complete
or partial remission with other medication. It is unknown
whether MMF alone or in combination is helpful in inducing
remission. The ongoing INTENT Study in Germany is a ran-
domized prospective trial to evaluate the potential steroid-
sparing role of MMF in the initial treatment of steroid-
sensitive idiopathic nephrotic syndrome in children
(EudraCT No. 2014-001991-76). The INTENT Study trans-
fers the beneficial effects of MMF in preserving remission to
the period of initial treatment by substituting prednisone with
MMF for the rest of the initial treatment period of 12 weeks
(as soon as clinical remission is achieved). If this approach
proves to be not inferior to the standard treatment with pred-
nisone (in terms of time to first relapse and number of relapses
within 2 years of follow-up), it has the potential to change the
initial standard treatment of nephrotic syndrome to a less toxic
approach.
In conclusion, MMF is a valuable therapeutic option in
children with SSNS exeriencing frequent relapses or steroid
dependency. As a steroid-sparing agent, MMF is recommend-
ed for patients with FRNS/SDNS experiencing steroid toxicity
by the KDIGO expert working group and the GPN expert
group. MMF has immunosuppressive and antiproteinuric ef-
fects, is generally well tolerated, and lacks nephrotoxicity.
Therapy should be guided by drug monitoring to avoid re-
lapses due to underdosing. In SRNS patients, MMF is also
beneficial in selected patients, but more experience is required
to establish the most effective combination or sequential ther-
apy to achieve complete or partial remission. MMF is terato-
genic and contraceptive advice is required in females. As in all

patients requiring long-term immunosuppression, regular
follow-up and a high index of suscpicion are warranted, even
in patiens achieving remission, to recognize and treat adverse
events and complications.
Multiple-choice questions (answers are
provided following the reference list)
1. What statement on nephrotic syndrome in childhood is
correct?
a) Idiopathic nephrotic syndrome is by far the least fre-
quent glomerular disease in childhood.
b) About a half of patients with relapses have frequently
relapsing nephrotic syndrome with one third to one
half of these being steroid dependent.
c) Azathioprine is the preferred steroid-sparing agent for
treatment of nephrotic syndrome in childhood.
d) Prolonged use of steroids for treatment of nephrotic
syndrome in childhood is generally tolerated without
any side effects.
e) There is broadly based consensus of steroid-sparing
treatment of nephrotic syndrome in childhood.
2. Mycophenolic acid is
a) an ester prodrug of Mycophenolate Mofetil
b) acts as an inhibitor of inosine monophosphate
dehydrogenase
c) counteracts the expansion of mesangial matrix
d) has no systemic toxicity at all
e) seems to have an antiproteinuric effect
Which statements are correct?
a) Statements 1 and 2 are correct
b) All statements are correct
c) Statements 2, 3 and 5 are correct
d) Statements 2 to 5 are correct
e) Statements 2 and 5 are correct
3. What statement on pharmacokinetics of mycophenolic
acid is false?
a) There is a poor correlation between MMF dose and MPA
exposure.
b) The pharmacologically inactive 7-O-MPA glucuronide
(MPAG) is the major metabolite of MPA.
c) MPA exhibits significant inter- and intra-patient variabil-
ity in drug pharmacokinetics.
d) Therapeutic drug monitoring of Mycophenolate Mofetil
plays no role in children with nephrotic syndrome.
Pediatr Nephrol
e) Exposure to MPA needs to be higher in children with
nephrotic syndrome to be efficacious than in pediatric
renal transplant recipients.
4. What statement on the therapeutic properties of
Mycophenolate Mofetil (MMF) is correct?
a) MMF is not a therapeutic option in children with
steroid-sensitive nephrotic syndrome experiencing
frequent relapses or steroid dependency.
b) When using MMF as long-term immunosuppression,
no further follow-up to detect potential side effects is
warranted.
c) MMF is always beneficial in patients with steroid-
resistant nephrotic syndrome.
d) The KDIGO expert working group has not recom-
mended MMF for patients with FRNS/SDNS
experiencing steroid toxicity.
e) MMF has immunosuppressive and antiproteinuric
effects.
5. Critically reviewing published studies on Mycophenolate
Mofetil (MMF) for sustained remission in nephrotic syn-
drome one has to consider that
a) there are important limitations to the interpretation and
comparability of published studies including study de-
sign, sample size, patient selection, clinical endpoints,
carry-over effects and duration of follow-up.
b) it is not possible to finally determine efficacy of MMF
from the published uncontrolled studies,
c) it is currently unclear how long patients with fre-
quently relapsing nephrotic syndrome, steroid-
dependent nephrotic syndrome or steroid-resistant ne-
phrotic syndrome should be treated with MMF.
Which statements are correct?
a) All of the above statements are correct.
b) None of the above statements is correct.
c) Only statement 1 is correct.
d) Statements 2 and 3 are correct.
e) Statements 1 and 3 are correct.
6. What statement on principal limitations of clinical trials in
patients with relapsing nephrotic syndrome is correct?
a) All steroid-sparing drugs used for treatment of the
nephrotic syndrome have only weak immunosuppres-
sive properties.
b) The idiopathic nephrotic syndrome may follow its
natural course and may resolve with time. Treatment
effects may thus be falsely attributed to a particular
medication.
Pediatr Nephrol
c) Pharmacokinetics of mycophenolic acid do not show
large inter- and intra-individual variability.
d) The clinical response to steroids is always constant.
e) The disease affects mainly girls, and results of all
studies may be biased by a preponderance of female
participants.
Compliance with ethical standards
Conflict of interest Uwe Querfeld declares that he has no conflict of
interest. Lutz T. Weber has received financial support (travel grants) from
Astellas.
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Answers
1. b; 2. c; 3. d; 4. e; 5. a; 6. b