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Pediatric Nephrology

https://doi.org/10.1007/s00467-017-3846-6

ORIGINAL ARTICLE

Mycophenolate mofetil following glucocorticoid treatment


in Henoch-Schönlein purpura nephritis: the role of early initiation
and therapeutic drug monitoring
Agnes Hackl 1 & Jan U. Becker 2 & Lisa M. Körner 1 & Rasmus Ehren 1 & Sandra Habbig 1 &
Eva Nüsken 1 & Kai-Dietrich Nüsken 1 & Kathrin Ebner 1 & Max C. Liebau 1,3,4 &
Carsten Müller 5 & Martin Pohl 6 & Lutz T. Weber 1

Received: 29 May 2017 / Revised: 2 November 2017 / Accepted: 3 November 2017


# IPNA 2017

Abstract
Background Henoch-Schönlein purpura (HSP) is the most common vasculitis in childhood and traditionally considered as a self-
limiting disease. However, renal involvement can unfavorably determine long-term prognosis. The reported regimens to treat
HSP nephritis (HSPN) are diverse, indicating that the most effective treatment remains controversial.
Methods This retrospective, single-center study involved 18 patients presenting with HSPN and nephrotic-range proteinuria. We
aimed to investigate the efficacy and safety of mycophenolate mofetil (MMF) and identify a cut-off level for estimated myco-
phenolic acid area under the curve (eMPA-AUC0-12h) values, which can predict complete remission with high sensitivity.
Results Despite prior insufficient therapeutic response to corticosteroids, 89% of patients showed a significant decrease in
proteinuria after 1 month of MMF treatment. None of them relapsed during treatment; however, two children relapsed after
discontinuation. Based on results of a receiver operating characteristic (ROC) analysis, an eMPA-AUC0–12h >56.4 mg*h/l was a
predictor for complete remission within 3 months (80% sensitivity, 83.3% specificity, p = 0.035). During MMF administration,
we encountered no adverse event requiring discontinuation of treatment.
Conclusion Our study demonstrates that MMF is a safe and potentially effective secondary treatment option for children with
HSPN to achieve and maintain long-term remission without serious side effects. To achieve complete remission within 3 months,
resolve severe inflammatory glomerular lesions, and avoid progression to chronic kidney disease, we propose timely diagnosis
and early initiation of MMF with an eMPA-AUC0–12h value of 56.4 mg*h/l.

Electronic supplementary material The online version of this article Keywords Mycophenolic acid . Therapeutic drug monitoring .
(https://doi.org/10.1007/s00467-017-3846-6) contains supplementary Pre-dose level . Cut-off of eMPA-AUC0-12h . Mechanism of
material, which is available to authorized users. action

* Agnes Hackl
agnes.hackl@uk-koeln.de
Abbreviations
1
Pediatric Nephrology, Children’s and Adolescents’ Hospital, ACEi Angiotensin-converting enzyme inhibitors
University Hospital of Cologne, Kerpener Street 62, ARB Angiotensin II receptor blockers
50937 Cologne, Germany BSA Body surface area
2
Institute of Pathology, University Hospital of Cologne, CI Confidence interval,
Cologne, Germany CKD Chronic kidney disease
ESRD End-stage renal disease
3
Nephrology Research Laboratory, Department II of Internal GTP Guanosine-5′-triphosphate
Medicine, University Hospital of Cologne, Cologne, Germany HSP Henoch-Schönlein purpura
4
Center for Molecular Medicine, University Hospital of Cologne, HSPN Henoch-Schönlein purpura nephritis
Cologne, Germany IgACI Immunoglobulin A circulating immune complex
IMPDH Inosine-5′-monophosphate dehydrogenase
5
Department of Therapeutic Drug Monitoring, Centre of IS therapy Immunosuppressive therapy
Pharmacology, University Hospital of Cologne, Cologne, Germany MMF Mycophenolate mofetil
6
Department of General Pediatrics, Adolescent Medicine and MP Methylprednisolone
Neonatology, Medical Center - Faculty of Medicine, University of MPA-C0 Pre-dose level of mycophenolic acid
Freiburg Germany, Freiburg, Germany
Pediatr Nephrol

eMPA-AUC0-12h Estimated mycophenolic acid–area under the However, these drugs carry the risk of severe side effects, such
concentration versus time curve
as gonadotoxicity, bone marrow toxicity, nephrotoxicity, neu-
NA Not applicable
PU Proteinuria rotoxicity, and hyperuricemia.
RAAS Renin–angiotensin–aldosterone system Also, for safety reasons in this vulnerable population, my-
ROC Receiver operating characteristic cophenolate mofetil (MMF) was proposed as an alternative
TDM Therapeutic drug monitoring
therapeutic option. It is a powerful inhibitor of lymphocyte
UTI Urinary tract infection
proliferation [17] and has been successfully used for >20 years
in transplantation medicine. MMF has recently gained popu-
larity as a glucocorticoid- and calcineurin-inhibitor-sparing
Introduction agent for the treatment of children with idiopathic nephrotic
syndrome [18–21]. Lately, the first reports of its use in HSPN
Henoch-Schönlein purpura (HSP) is the most common vascu- have been published in adults [22–24] and children [25, 26].
litis in childhood, with an incidence of 6.1:100,000 children However, pediatric experience is still limited.
<17 years of age and showing a male dominance [1–4]. The Our goal was to assess the efficacy and safety of MMF in
disease is traditionally considered as self-limiting, but renal HSPN presenting with nephrotic-range proteinuria and evalu-
involvement, which has been reported in 46% of patients ate the beneficial effect of early initiation of therapy adjusted
[5], can unfavorably determine long-term prognosis. In spe- by therapeutic drug monitoring (TDM).
cialized centers, 20% of patients with renal symptoms prog-
ress to end-stage renal disease (ESRD) [2], constituting 1% of
the pediatric kidney transplant population [6]. Methods
The reported regimens of HSP nephritis (HSPN) therapy
are diverse, indicating that the most effective treatment re- Patients
mains controversial. The Kidney Disease: Improving Global
Outcomes (KDIGO) guidelines suggest treatment with Our work is a single-center, retrospective study conducted at the
angiotensin-converting enzyme inhibitors (ACEi) or angio- Division of Pediatric Nephrology, Children’s and Adolescents’
tensin II receptor blockers (ARB) for patients with proteinuria Hospital, University Hospital of Cologne, Germany. In the last
>0.5 g/d/1.73m2 body surface area (BSA). Furthermore, in 10 years (from December 2006 to December 2016), 18 children
patients with nephrotic-range proteinuria, orally administered with HSP having nephrotic-range proteinuria (defined as
corticosteroids are recommended for 6 months. Due to lack of >40 mg/m2BSA/h or 2 g/gCrea—in most cases determined
strong evidence, immunosuppressive (IS) therapy is only a with a 24-h urine collection and in a few cases in spot urine
weak suggestion (2D), even in case of nephrotic-range pro- samples) despite renin–angiotensin–aldosterone system
teinuria with deteriorating kidney function [7]. It is important (RAAS) blockade were biopsied in our center confirming the
to note that this guideline refers to studies conducted in adult diagnosis of HSPN (Fig. 1). The study was performed in accor-
patients with immunoglobulin A (IgA) nephritis. dance with the Declaration of Helsinki 2013.
Additionally, Cochrane analyses, derived from generally
low-quality evidence in adults as well as children, found no Histological analysis
strong evidence of benefit for any of the investigated treatment
approaches in HSPN [8]. However, several retrospective and a Sixteen of 18 first renal biopsies were processed at the Renal
few controlled prospective studies focusing on the pediatric Pathology Laboratory, University Hospital of Cologne,
population with HSPN reported a beneficial role of IS therapy. Germany, using standard techniques for light microscopy, im-
Early corticosteroid treatment in prospective studies signifi- munofluorescence, and electron microscopy. Renal biopsies
cantly reduced the odds of developing renal disease [9–11]. were examined by the same pathologist (JUB) and classified in
Furthermore, prompt initiation of prednisolone orally in com- accordance with the modified Oxford classification [27] and the
bination with cyclophosphamide may be beneficial [12]. International Study of Kidney Disease in Children (ISKDC)
However, cyclophosphamide alone was not proven to be ef- scoring system [28]. The two remaining biopsies (patients 11
fective in a randomized, prospective trial [13]. On the con- and 16) had been processed elsewhere. On average, renal biopsy
trary, cyclosporin A (CyA) treatment was effective in HSPN was performed 54.0 ± 80.7 days after the first diagnosis of HSP.
showing nephrotic-range proteinuria, not only in combination
with steroids [14] but also as monotherapy [15]. It was safe Treatment protocol
and not inferior to corticosteroid treatment according to a ran-
domized open-label clinical trial [15]. Finally, a regimen of Due to persisting proteinuria (either in nephrotic range or con-
mizoribine with steroids seemed to be effective in ameliorat- stantly increasing) under RAAS blockade (ramipril in 14 pa-
ing proteinuria and the histological severity of HSPN [16]. tients, dual RAAS blockade with ramipril and losartan in four
Pediatr Nephrol

Fig. 1 Patient selection. This


retrospective, single-center study
paents with HSP
involved 18 patients presenting with proteinuria
with Henoch-Schönlein purpura
nephritis (HSPN) and nephrotic-
range proteinuria treated with RAAS inhibion
mycophenolate mofetil (MMF)
after insufficient therapeutic recovery proteinuria either in nephroc range or with increasing tendency
response to renin–angiotensin–

61.9 ± 95.4 days


aldosterone system (RAAS)
blockade and corticosteroids.
*One patient received paents with biopsy proven HSPN referred to our department for further therapy
corticosteroids orally, and seven or
paents referred to our department for biopsy and further treatment
received corticosteroids IV at a
dosage of 1–2 mg/kg per day
i.v./oral steroid therapy

85.0 ± 88.0 days


before referral to our department.
PU proteinuria, BSA body surface 18 paents
area recovery with biopsy proven HSPN
(mean se albumin: 34.5g/l;
mean PU: 113mg/m2BSA/h )

i.v. steroid pulse + oral steroids

proteinuria either in nephroc range or less than 50% decrease in


proteinuria

21.9 ± 17.5 days


18 paents with HSPN
(mean se albumin: 36.9g/l;
mean PU: 69mg/m2BSA/h)

MMF

2 responders
2 inial non-responders 14 stable responders relapsed aer
disconnuaon

children) and on the basis of histological confirmation of 0 (MPA-C0) 30 and 120 min after drug intake. Estimation of
HSPN, pulsed methylprednisolone (MP) was initiated on aver- individual estimated mycophenolic acid–area under the
age 61.9 ± 95.4 days after the first diagnosis (300 mg/m2BSA/ concentration-time curve profiles (eMPA-AUC0–12h) was de-
day on 3 alternate days), followed by prednisone at 60 mg/ rived from plasmatic MPA-concentrations and calculated based
m2BSA/day for 3 weeks, then 40 mg/m2BSA/day on alternate on a two-compartment model using the pharmacokinetic soft-
days for 4 weeks [29]. On average, 3 weeks (21.9 ± 17.5 days) ware package MW/Pharm (version 3.5).
after initiation of pulsed MP, the course of proteinuria was re-
evaluated, and on the basis of this evaluation (<50% decrease in Management of relapses and adverse events
proteinuria or proteinuria >40 mg/m2BSA/h or 2 g/gCrea) a
decision was made to start MMF treatment. Thus, MMF was Proteinuria was monitored at home by dipstick analysis and
introduced as the second-line therapy on average 85.0 ± 88. 24-h urine collection on regular follow-up visits. Partial remis-
0 days after the first diagnosis of HSP, 33.8 ± 47.6 days after sion was defined as proteinuria between 4 and 40 mg/m2BSA/
the diagnosis of HSPN, and 21.9 ± 17.5 days after initiation of h or 0.2–2 g/gCrea and complete remission as proteinuria
pulsed MP. The initial dose of MMF was 800–1200 mg/ <4 mg/m2BSA/h or 0.2 g/gCrea. Relapse was defined by pro-
m2BSA/day divided into two daily doses, which was later ad- teinuria >40 mg/m2BSA/h or 2 g/gCrea, or deterioration of
justed according to the result of repeated TDM (performed kidney function. A relapse was treated again with the thera-
within 3 months of therapy onset and yearly thereafter). TDM peutic regimen described above. Adverse events, such as di-
profiling was started 12 h after the last dose of MMF. For TDM, arrhea (three or more watery stools per day), gastrointestinal
we used a limited sampling strategy based on measurements at pain, weight loss, anemia, leukocytopenia, thrombocytopenia,
Pediatr Nephrol

and infections were carefully monitored. In case of gastroin- After pulsed MP, a regular urine check was performed
testinal toxicity not otherwise explained, hemoglobin levels weekly in the first month and thereafter every second week.
<8.0 g/dl, leukocyte counts <3.5 gpt/l, or thrombocyte count On average, 3 weeks after initiation of pulsed MP, ten of 18
<150 gpt/l, MMF therapy was discontinued. patients still had nephrotic-range proteinuria (>40 mg/
m2BSA/h or 2 g/gCrea), and the remaining patients still had
mild to moderate proteinuria (4–40 mg/m2BSA/h or 0.2-2 g/
Statistical analysis
gCrea), with <50% decrease of initial proteinuria. Until this
time, we found no significant reduction in proteinuria (p =
Data were interpreted as mean and standard deviation (SD).
0.053 or p = 0.151 in case of unit mg/m2BSA/h or g/gCrea,
The relation between variables was examined with either
respectively) or in serum albumin (p = 0.061). Therefore, pa-
Pearson’s or Spearman’s correlation, depending on their dis-
tients were started on MMF after a mean of 85.0 ± 88.0 days
tribution. Paired Student’s t tests or Wilcoxon signed-rank
after presentation of HSP and 21.9 ± 17.5 days after initiation
tests were applied for data comparison likewise, depending
of pulsed MP. Thereafter, the mean duration of MMF therapy
on their distribution. To find the cut-off level of eMPA-
was 26.1 ± 11.5 months and mean follow-up after discontinu-
AUC0–12h indicating sensitivity and specificity for prediction
ation 32.9 ± 20.7 months. Two patients with initial ISKDC
of relapses, receiver operating characteristic (ROC) plots were
score of IIIa/b and crescent formation did not improve with
created. To compare blood results and clinical data over the
MMF treatment. However, if a child improved (89%), no re-
course of time, repeated measures analysis of variances
lapse developed under MMF therapy. Two children experi-
(ANOVA) were used, which were corrected by Greenhouse–
enced a relapse after discontinuation (after 2 and 11 months,
Geisser correction by violation of the assumption of spheric-
respectively) (Table 1) and were treated again with the thera-
ity. Bonferroni-corrected t tests were performed as post hoc
peutic regimen described above.
tests. To assess other factors (time between diagnosis of HSP
The most important effect of MMF treatment, a rapid and
and initiation of MMF therapy in days, Oxford total, Oxford
significant decrease in proteinuria and increase in serum albu-
crescent, and ISKDC score) that have eventual influence on
min, was seen after 1 month (Fig. 2, Table 3), without deteri-
early remission after MMF treatment, linear regression analy-
oration of kidney function in short- or long-term follow-up
sis was performed. Results with p < 0.05 were considered sta-
(Supplementary Table S1).
tistically significant. IBM SPSS (version 24) and Microsoft
During MMF treatment, there was no significant change in
Excel were used for statistical analysis.
hemoglobin levels or thrombocyte counts (Supplementary
Observed individual MPA plasma concentrations were
Table S1). However, a significant decline—in general, with-
fitted to an open two-compartment model employing a
out leaving the normal range—was observed in leukocyte
Bayesian estimation method, taking into account observed
count between initiation of MMF therapy and the later time
plasma levels and pharmacokinetic (PK) population parame-
points (months 1, 3, 12, last follow-up) (Supplementary
ters. Using this two-stage PK analysis approach, an estimated
Table S1).
individual Bayesian posterior PK parameter (eMPA-AUC0-
MPA daily dose and MPA-C0 correlated significantly with
12h) was calculated (US Department of Health and Human
the eMPA-AUC0-12h (p = 0.001), but rather weakly (r2 =
Services, Food and Drug Administration. Guidance for
0.412 and r2 = 0.188, respectively).
Industry on Population Pharmacokinetics, 1999). eMPA-
Seeking the cause of nonresponse to MMF, we compared
AUC0-12h values were targeted to be >30 mg*h/l [30].
the two nonresponders with the other 16 patients whose pro-
teinuria improved during therapy. However, no remarkable
differences in the following values were found during the
Results observation period: MMF dose was 1011 [95% confidence
interval (CI) 607–1416] mg/day vs. 916 (95% CI 840–992)
Table 1 represents the main clinical characteristics of 18 chil- mg/day, MPA-C0 amounted to 2.5 (95% CI 0.8–4.2) mg/l vs.
dren with HSPN who developed nephrotic-range proteinuria 2.8 (95% CI 2.0–3.7) mg/l and eMPA-AUC0-12h values were
and were treated with MMF as second-line therapy. Mean age 49.0 (95% CI 26.0–72.0) mg*h/l vs. 52.6 (95% CI 44.2–61.1)
of our patients at disease onset was 9.6 ± 3.4 years, with a mg*h/l—nonresponders vs. responders, respectively.
strong male predominance (14 boys, 4 girls). The children were To find a cut-off level of eMPA-AUC0-12 indicating sensi-
followed up in our center for a mean of 42.2 ± 28.0 months. tivity and specificity for predicting complete remission at
Table 2 demonstrates the histological findings in 16 pa- month 3, year 1, and year 2, ROC curves were created. A
tients; 63% of biopsies showed advanced changes according cut-off of 56.4 mg*h/l showed a sensitivity of 80% and a
to ISKDC (ISKDC ≥ III), which were all accompanied by specificity of 83.3% to discriminate children in complete re-
crescent formation according to the modified Oxford mission from the ones with proteinuria >4 mg/m2BSA/h
classification. (ROC–AUC 0.833, p = 0.035) (Fig. 3a, Table 4a) and a
Pediatr Nephrol

Table 1 Main clinical characteristics of 18 children with Henoch-Schönlein purpura (HSP) who developed nephrotic-range proteinuria and were
treated with mycophenolate mofetil (MMF)

Age at Gender Time between HSP Duration of Total Follow-up after Favorable Relapse Relapse after
HSP onset and MMF MMF follow-up MMF response to during discontinuation
onset initialization (days) therapy (months) discontinuation MMF MMF of MMF therapy
(years) (months) (months) therapy therapy

1. 15.0 F 43 17.0 37.1 20.1 No NA NA


2. 8.4 M 43 18.0 61.0 43.0 No NA NA
3. 11.5 M 45 32.0 32.0 NA Yes No no
4. 5.9 M 76 NA 20.9 NA Yes No NA
5. 8.2 F 46 24.0 39.5 NA Yes No yes
6. 12.4 M 72 NA 16.3 NA Yes No NA
7. 10.0 M 78 25.4 40.1 14.7 Yes No No
8. 9.0 M 28 24.0 24.0 NA Yes No No
9. 4.9 F 9 19.8 64.5 44.7 Yes No No
10. 10.1 M 240 54.0 70.7 16.7 Yes No No
11. 5.5 F 36 23.9 23.9 NA Yes No No
12. 10.2 M 361 25.0 33.9 8.9 Yes No No
13. 14.0 M 120 8.0 21.1 NA Yes No Yes
14. 3.4 M 90 NA 6.2 NA Yes No NA
15. 15.4 M 47 15.0 15.0 NA Yes No No
16. 8.8 M 40 41.6 95.7 54.0 Yes No No
17. 8.7 M 46 26.5 50.8 24.4 Yes No No
18. 10.8 M 110 37.7 107.0 69.3 Yes No No
mean ± SD 9.6 ± 3.4 14 M; 85.0 ± 88.0 26.1 ± 11.5 42.2 ± 28.0 32.9 ± 20.7 88.9% 0% 15.4%
4F

MMF mycophenolate mofetil, M male; F female, SD standard deviation, NA not applicable

sensitivity of 75% and specificity of 83.3% to discriminate Discussion


children in complete remission from those with proteinuria
>0.2 g/gCrea (ROC–AUC 0.823, p = 0.017) (Fig. 3b, Results of our retrospective, single-center study show that MMF
Table 4b) 3 months after initiation of MMF. At later time in combination with an initial course of corticosteroids may be
points (1 and 2 years after onset of MMF therapy), ROC curve an effective agent to achieve and maintain remission in children
analysis failed to show an eMPA-AUC0-12 dependent advan- with HSPN and nephrotic-range proteinuria. Applying TDM
tage (data not shown). and adjusting eMPA-AUC0-12h to the value of 56.4 mg*h/l at
According to our experience, mild to moderate gastrointes- the onset of therapy, it is possible to achieve complete remission
tinal disturbances, mild anemia, and upper respiratory already within 3 months without severe adverse effects.
infections were most frequently reported or measured during
MMF treatment. Comparing patients with eMPA-AUC0–12h Treatment options
values below or above 56.4 mg*h/l, we found no relevant
differences in frequency of adverse events during the first HSPN in children was traditionally considered a self-limiting
(most vulnerable) 3 months of treatment. Although diarrhea disease requiring only supportive treatment. However, after
was more frequent in patients with eMPA-AUC0-12h values long-term follow-up studies revealed the high rate of late-
>56.4 mg*h/l, weight loss occurred with the same frequency developing chronic kidney disease (CKD) in this population
in both groups. Laboratory parameters did not differ [31], the need for effective anti-inflammatory treatment in sub-
significantly (Supplementary Table S2). Importantly, diarrhea groups is generally accepted [32]. CyA treatment in HSPN with
regressed after dividing daily MMF into four doses, and nephrotic-range proteinuria, however, has not found its way into
anemia resolved spontaneously with time. Other factors KDIGO guidelines [7], despite its promising effects [14, 15].
(time between diagnosis of HSP and initiation of MMF KDIGO guidelines suggest treatment with RAAS inhibitors for
therapy in days, Oxford total, Oxford crescent, and ISKDC 3-6 months and addition of steroids orally for 6 months in pa-
score) did not influence early remission after MMF treatment tients with persisting nephrotic-range proteinuria. Only in case of
(data not shown). crescent formation in >50% of glomeruli is the use of
Pediatr Nephrol

Table 2 Histological characteristic of 16 children with Henoch- HSPN accompanied by nephrotic-range proteinuria, pulsed MP
Schönlein purpura (HSP) who developed nephrotic-range proteinuria
therapy was administered directly after biopsy, resulting in slight
and were treated with mycophenolate mofetil (MMF). The table
demonstrates histological findings according to the Oxford improvements in proteinuria, but therapeutic response until re-
classification and International Study of Kidney Disease in Children evaluation was insufficient. However, we cannot formally rule
(ISKDC) at the first renal biopsy and long-term outcome out a late effect of pulsed MP on the course of the disease [10] or
Oxford ISKDC clinically assessed outcome a more favorable therapeutic effect of pulsed MP at a higher
dose, as others recommend [10, 15]. MMF was hence introduced
1. M1;E1;S1;T2;C2 IIIb Nonresponder as early as 3 months (85 ± 88.0 days) after disease onset to re-
2. M0;E1;S1;T0;C1 IIIa Nonresponder duce disease activity (endocapillary inflammation and crescent
3. M0;E0;S1;T0;C2 IVa good formation). However, this critical time frame may be further
4. M0;E1;S0;T0;C1 III good reduced by 4–6 weeks, as some authors suggest [2, 10, 12, 15,
5. M1;E1;S1;T0;C2 IIIb relapse after MMF discontinuation 25, 26, 34], if future referrals of patients are carried out resulting
6. M1;E1;S1;T0;C2 IIIb good in timely diagnostic kidney biopsy and consecutive treatment
7. M0;E1;S0;T0;C0 II good without delay.
8. M1;E1;S0;T0;C0 II good
9. M1;E1;S1;T0;C0 II good Mechanism of action
10. M0;E0;S0;T0;C0 II good
12. M0;E0;S0;T0;C0 II good The rationale for using MMF therapy in HSPN patients is the
13. M0;E0;S0;T0;C1 IIIa relapse after MMF discontinuation well-known mechanism of its active moiety, MPA, which in-
14. M0;E1;S1;T0;C1 III good hibits lymphocyte inosine-5′-monophosphate dehydrogenase
15. M1;E0;S1;T0;C0 II good (IMPDH). Thereby, it strongly decreases guanosine-5′-triphos-
17. M0;E0;S1;T0;C2 III good phate (GTP) concentrations essential for lymphocyte prolifera-
18. M0;E0;S1;T0;C1 III good tion [17]. In HSPN, MPA can decrease IgA production of lym-
phocytes and reverse even the IgA1-aberrant O-glycosylation
M mesangial hypercellularity, E endocapillary hypercellularity, S segmen-
tal glomerulosclerosis, T tubular atrophy/interstitial fibrosis, C crescent
level in peripheral lymphocytes [35], resulting in reduced de-
formation position of subendothelial and mesangial IgA-containing im-
mune complexes. It is less known, but also important in the
cyclophosphamide a weak suggestion. This guideline refers to pathomechanism of mesangial proliferation, that MPA also sig-
studies conducted in adult patients with IgA nephritis, which is a nificantly depletes GTP levels in monocytes [17]. Beyond this
much more chronic, indolent disease, with continuous mesangial classical effect, a vast body of evidence has shown that this
proliferation in contrast to HSPN, with a high frequency of cres- agent effects not only immune cells but also nonimmune cells
cent formation, endocapillary infiltration of neutrophils, and sub- [36]. MPA exerts a direct inhibitory effect on secretion of osteo-
sequent acute and deteriorating episodes [33]. We therefore pontin, fibronectin, and collagen type I in stimulated mesangial
followed a stricter treatment protocol, which aims to reduce de- cell cultures in vitro [37, 38] and on production of collagen type
lay in IS treatment initiation and prevent undertreatment of cres- III in mesangial cells in vivo after 5/6 nephrectomy [39].
centic lesions. Accordingly, in our patients with biopsy-proven Furthermore, Takeda et al. showed that in an anti-glomerular-
basement-membrane (GBM) antibody-induced rat model, 14-
day MMF treatment prevented glomerular crescent formation
50 120
and glomerulosclerosis if MMF treatment was started on day 1,
proteinuria (mg/m2BSA/h)

47
100 but not when started 5 days after the anti-GBM antibody injec-
tion [40].
se albumin (g/l)

80
44
60
41
40 Clinical data and laboratory values
38
20
In the literature, 15 children with HSPN treated with MMF due
35 0 to steroid-resistant nephrotic-range proteinuria have been de-
scribed so far (Table 5). It is well known that nephrotic-range
proteinuria lasting >3 months has a significant adverse effect on
renal outcome [31]. Accordingly, in the children mentioned
Fig. 2 Changes in serum albumin (gray) and proteinuria (black) in the course
of disease. To compare parameters in the first year, repeated measures
above as well as our patients, the decision to initiate MMF
analysis of variance (ANOVA) was performed. BSA body surface area. therapy was made within 3 months after disease onset to reduce
* P < 0.05 vs. initiation of mycophenolate mofetil (MMF) therapy. disease activity and improve long-term renal outcome. In the
Pediatr Nephrol

Table 3 Changes in serum albumin and proteinuria in the course of disease. To compare parameters, in the first year, repeated measures analysis of
variance (ANOVA) was performed

at start of MMF month 1 month 3 month 6 month 12

Serum albumin (g/l) 36.9 ± 5.1 40.0 ± 4.0 * 41.9 ± 3.7 * 43.9 ± 4.2 * 44.4 ± 3.8 *
proteinuria (mg/m2BSA/h) 69.0 ± 46.5 24.9 ± 28.9 * 18.6 ± 17.7 * 12.4 ± 10.8 * 10.2 ± 11.9 *
proteinuria (g/gCrea) 2.8 ± 2.3 1.2 ± 1.4 * 0.8 ± 0.8 * 0.5 ± 0.4 * 0.4 ± 0.5 *

BSA body surface area, MMF mycophenolate mofetil


*P < 0.05 vs. initiation of MMF therapy

two pediatric studies [25, 26] listed in Table 5, MMF therapy Our patients showed a significant decrease in proteinuria
was administered for either 4 and 12 months, respectively, at a and increase in serum albumin as early as 1 month after initi-
dosage of 20–30 mg/kg per day. Both studies achieved a favor- ation of therapy, which stayed in normal range for the rest of
able response to MMF in 100% of cases and found no relapse the follow-up (42.2 ± 28.0 months). However, only one pa-
during or after MMF treatment. However, the small number of tient reached complete remission within the first month and
patients is certainly a limitation of both studies. In contrast to eight patients within 3 months. The time course of proteinuria
these reports, our patients were treated with MMF for a longer reduction in response to MMF treatment is in accordance with
period—at least 6 months of complete remission (proteinuria the limited published data available. As early as 1 month of
<4 mg/m2BSA/h or 0.2 g/gCrea, no efflorescences, no joint MMF treatment initiation, one can expect a significant im-
pain) before discontinuing MMF therapy. The higher ratio of provement in proteinuria [23–25]. However, achieving com-
non-responders (11.1%) as well as relapses after MMF discon- plete remission (< 4 mg/m2BSA/h or 0.2 g/gCrea) takes more
tinuation (15.4%) in our study may be explained by the larger time: 15.4 ± 17.2 months in our patients, 6.1 ± 3.7 months in
study population than in the two previous reports. Comparison the cohort described by Ren et al. [23], and 11 ± 1.7 months in
of our results with data of adult patients with HSPN is difficult, the cohort described by Du et al. [25]. We observed a signif-
since adult nephrologists initiate MMF therapy later than pedi- icant decline in leukocyte count after initiating MMF therapy,
atric nephrologists. Nevertheless, the higher patient number in with no overt risk of leukocytopenia. It is highly possible that
the adult studies gives us a more realistic picture of the percent- leukocyte counts of our patients were stimulated by the pre-
age of non-responders and relapse rate during and after MMF ceding use of corticosteroids that diminished with time. All
treatment [23, 24], which were comparable with our other monitored parameters were in the physiological range
experiences. and did not change relevantly within the observation period.

A B
Sensivity

Sensivity

AUC=0.833 AUC=0.823
p=0.035 p=0.017

1-Specificity 1-Specificity
Fig. 3 Receiver operating characteristics (ROC) plot calculated for proteinuria >4 mg/m2 body surface area (BSA)/h (ROC-AUC: 0.833,
estimated mycophenolic acid area under the curve (eMPA–AUC0-12h) p = 0.035). b Discrimination of children in complete remission from
3 months after initiation of mycophenolate mofetil (MMF) therapy. a those with proteinuria >0.2 g/gCrea (ROC–AUC: 0.823, p = 0.017).
Discrimination of children in complete remission from children with
Pediatr Nephrol

Table 4 Receiver operating characteristics (ROC) plot calculated for with nephrotic syndrome [20, 21, 43], we used this parameter
estimated mycophenolic acid area under the curve (eMPA-AUC0-12h)
for monitoring, which necessitated a dose adjustment in 50%
3 months after initiation of mycophenolate mofetil (MMF) therapy. A
cut-off of 56.4 mg*h/l showed a sensitivity of 80% and a specificity of of patients. ROC curve analysis showed that it is essential in
83.3% to discriminate children in complete remission from children with the first 3 months to reach an eMPA-AUC0-12h close to or
proteinuria >4 mg/m2 body surface area (BSA)/h (p = 0.035) and a >56.4 mg*h/l, since complete remission can be achieved with
sensitivity of 75% and specificity of 83.3% to discriminate children in
high sensitivity (80%) and specificity (83.3%) within
complete remission from those with proteinuria >0.2 g/gCrea (p = 0.017)
3 months. This eMPA-AUC0–12h is at the upper limit of the
eMPA-AUC (mg*h/l) Sensitivity 1-Specificity target range recommended in immunosuppressive combina-
tion therapy after kidney transplantation (30–60 mg*h/l [30])
ROC curve analysis for complete remission
(proteinuria <4 mg/m2BSA/h) at month 3
and in line with the suggestion of higher target ranges in chil-
32.2 1.000 0.667
dren with idiopathic nephrotic syndrome on MMF monother-
apy (> 50 mg*h/l [20], > 45 mg*h/l [21, 43]). At later time
38.5 0.800 0.667
points (at the end of the first and second year of treatment), we
44.4 0.800 0.583
found no cut-off level for eMPA-AUC0-12h above which
49.1 0.800 0.500
MMF therapy would be more effective. Therefore, we hypoth-
53.5 0.800 0.417
esize that a lower eMPA-AUC0-12h target is sufficient later in
54.7 0.800 0.333
the course of treatment. This phenomenon might be explained
54.9 0.800 0.250
by the pathomechanism of HSPN; in the first acute phase of
56.4 0.800 0.167
disease, the inflammatory component is very pronounced,
59.9 0.600 0.167
while it subsides later on. Therefore, our result seems to be
64.3 0.600 0.083
in line with pathophysiological processes and emphasizes the
71.1 0.600 0.000
importance of early anti-inflammatory treatment.
ROC curve analysis for complete remission
(proteinuria <0.2 g/gCrea) at month 3
32.2 1.000 0.583
Adverse events
38.5 0.875 0.583
In order to analyze whether the children with an eMPA-
44.4 0.750 0.583
AUC0-12h above 56.4 mg*h/l develop adverse events more
49.1 0.750 0.500
frequently than those with an eMPA-AUC 0-12h below
53.5 0.750 0.417
56.4 mg*h/l, the two groups were compared. Although the
54.7 0.750 0.333
patients with higher exposure tended to experience diarrhea
54.9 0.750 0.250
more frequently, it was ameliorated after splitting the daily
56.4 0.750 0.167
MMF amount into four doses. This finding is in line with
59.9 0.625 0.167
the literature showing no associations between adverse events
63.1 0.625 0.083
and systemic concentration of total MPA in pediatric renal
71.1 0.500 0.000
transplant patients [44, 45]. An association was found only
between adverse events and the free (not albumin-bound)
MPA [41, 45], which was not determined in our study.
This finding is in line with the reported favorable profile of
MMF regarding potential side effects. Limitations

Therapeutic drug monitoring There are limitations to this retrospective study. It does not
exclusively prove the beneficial therapeutic effect of MMF,
The important role of TDM during MMF treatment has been because a late effect of pulsed MP on disease course cannot be
demonstrated after renal transplantation and in patients with ruled out. Furthermore, our children constituted the largest
nephrotic-range proteinuria. Measuring eMPA-AUC can re- published pediatric population with HSPN treated with
duce the risk of acute rejection in renal allograft recipients MMF. However, this patient number still must be considered
[41, 42]. Additionally, monitoring eMPA-AUC can prevent small, and no control group was available. HSPN is a rare
relapses in pediatric patients with frequently-relapsing ne- disease. Therefore, multicentric, prospective, randomized,
phrotic syndrome [20, 21, 43]. To further optimize our treat- TDM-based studies with larger patient numbers are difficult
ment protocol, TDM was applied for the first time—to the best to implement but are highly desirable to meet the standards of
of our knowledge - to treat HSPN with MMF. Considering evidence-based medicine. In particular, the proposed eMPA-
that eMPA-AUC0-12h reflects total body drug exposure and AUC 0-12h cutoff needs to be confirmed and validated
shows the strongest correlation with relapses in other diseases prospectively.
Pediatr Nephrol

Table 5 Summary of cases in the available literature on Henoch-Schönlein purpura nephritis treated with mycophenolate mofetil (MMF)

number of total control arm MMF arm time between disease duration initial dosage MMF favorable relapse relapse follow-up
patients follow-up onset and MMF of MMF of MMF adjusted response to during MMF after MMF after MMF
on MMF (months) initialization (days) therapy according MMF therapy (%) discontinuation discontinuation
(mo) to TDM therapy (%) (%) (months)

Dede et al. adult 1 42 none MMF, oral NI 24 2000 mg/day no 100 no 0 18


2008 steroids
[22]
Ren et al. 27 28 oral steroids MMF, oral NI NI 1000 mg/day no 78 no 0 NI
2012 steroids
[23]
Han et al. 33 28 oral steroids MMF, oral 135 12 1000 mg/day no 73 no 6 NI
2015 steroids
[24]
Du et al. pediatric 12 47 none MMF, MP 28 12 20–25 mg/kg/day no 100 no 0 35
2012 pulse, oral
[25] steroids
Nikibakhsh 3 8 none MMF, MP 24 4 30 mg/kg day no 100 no 0 5
et al. pulse, oral
2014 steroids
[26]
our patients 18 42 none MMF, MP 82 26 800–1200 mg/BSA yes 89 no 15 33
pulse, oral
steroids

NI no information, MP methylprednisolone, TDM therapeutic drug monitoring, BSA body surface area
Pediatr Nephrol

Conclusion 14. Park JM, Won SC, Shin JI, Yim H, Pai KS (2011) Cyclosporin A
therapy for Henoch-Schönlein nephritis with nephrotic-range pro-
teinuria. Pediatr Nephrol 26:411–417
Our retrospective single-center study demonstrates that fol- 15. Jauhola O, Ronkainen J, Autio-Harmainen H, Koskimies O, Ala-
lowing initial administration of corticosteroids, MMF treat- Houhala M, Arikoski P, Hölttä T, Jahnukainen T, Rajantie J, Ormälä
ment may represent a safe and potentially effective secondary T, Nuutinen M (2011) Cyclosporine a vs. methylprednisolone for
Henoch-Schönlein nephritis: a randomized trial. Pediatr Nephrol
treatment option for children with HSPN accompanied by
26:2159–2166
nephrotic-range proteinuria. Furthermore, we propose a time- 16. Kawasaki Y, Suyama K, Hashimoto K, Hosoya M (2011)
ly diagnosis and early initiation of MMF therapy with an Methylprednisolone pulse plus mizoribine in children with
eMPA-AUC0–12h target value of 56.4 mg*h/l to achieve com- Henoch-Schoenlein purpura nephritis. Clin Rheumatol 30(4):
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