OPEN The efficacy and safety of rituximab in

SUBJECT AREAS:
treating childhood refractory nephrotic
PAEDIATRIC KIDNEY
DISEASE syndrome: A meta-analysis
DRUG DEVELOPMENT
Zhihong Zhao1*, Guixiang Liao2*, Yongqiang Li1, Shulu Zhou1 & Hequn Zou1
PAEDIATRIC RESEARCH

1
Department of Nephrology, Institution of Urology and Nephrology, The Third Affiliated Hospital of Southern Medical University,
Received Guangzhou, 510630, China, 2Departments of Radiation Oncology, Nanfang Hospital, Southern Medical University, 1838 North
19 September 2014 Guangzhou Avenue, Guangzhou, 510515, China.
Accepted
2 January 2015 Rituximab is considered to be a promising drug for treating childhood refractory nephrotic syndrome.
Published However, the efficacy and safety of rituximab in treating childhood refractory nephrotic syndrome remain
3 February 2015 inconclusive. This meta-analysis aimed to investigate the efficacy and safety of rituximab treatment
compared with other immunosuppressive agents in children with refractory nephrotic syndrome. Three
randomized controlled trials and two comparative control studies were included in our analysis. The
included studies were of moderately high quality. Compared with other immunotherapies, rituximab
Correspondence and therapy significantly improved relapse-free survival (hazard ratio 5 0.49, 95% confidence interval [CI],
requests for materials 0.26–0.92, P 5 0.03). Rituximab also achieved a higher rate of complete remission (risk ratio,1.62; 95% CI,
should be addressed to 0.92 to 2.84, P 5 0.09) and reduced the occurrence of proteinuria (mean difference 5 20.25, 95% CI 5
20.29 to 20.21, P , 0.00001); however, a more targeted rituximab treatment did not significantly increase
H.Z. (hequnzou@
serum albumin levels and did not significantly reduce adverse events. Rituximab might be a promising
hotmail.com) treatment for childhood refractory nephrotic syndrome; however, the long-term effects and
cost-effectiveness of rituximab treatment were not fully assessed, and there were limited studies that
evaluated the clinical benefits of a concurrent infusion of rituximab plus a steroid compared with an
* These authors infusion of rituximab only. Additional studies are required to address these issues.
contributed equally to
this work.

N
ephrotic syndrome (NS) is a disorder characterized by large amounts of proteinuria, hypoalbuminemia,
edema, and hyperlipidemia1. This disorder affects the kidneys by increasing the permeability of the
glomerular basement membrane. NS occurs in 16 of every 100,000 children and is a major challenge
in pediatric nephrology2. Moreover, NS places a large financial burden on the patient’s family. Although most
affected children have steroid-sensitive nephrotic syndrome (SSNS), approximately 20% of children do not
achieve complete remission and have steroid-resistant nephrotic syndrome (SRNS)3. Moreover, 80%–90% of
children with SSNS experience relapses. Among these relapsing children, 50% relapse frequently and develop
steroid-dependent nephrotic syndrome (SDNS)4–6. The long-term use of corticosteroids can adversely affect
children’s growth and development7. The treatment of SRNS, SDNS, and SSNS remains challenging. Patients
with SRNS who do not achieve remission will develop end-stage renal failure. The exact pathogeneses of SRNS,
SDNS, and SSNS have not been fully elaborated, but immunological factors might play a vital role, and the use of
immunosuppressants and immunological treatment interventions appear to have achieved promising results7.
These immunosuppressants include cyclophosphamide8,9, chlorambucil10, cyclosporin11, levamisole12, and myco-
phenolate mofetil11. However, some of these immunosuppressants can have serious adverse effects such as
nephrotoxicity, hyperglycemia, headaches and dyslipidemia13. Novel drugs are needed to address these problems.
Rituximab is a monoclonal antibody that acts directly against CD20 expressed on B lymphocytes. It is widely
used to treat lymphoma14 and rheumatoid arthritis15. Rituximab administration results in rapid and sustained B
cell depletion. Several reports have proposed rituximab as a new treatment strategy for children with SDNS or
SSNS13,16,17. However, the use of rituximab in the treatment of steroid- and calcineurin inhibitor-dependent SSNS
requires further investigation. A single open-labeled, randomized controlled trial (RCT) that enrolled 54 children
with SDNS who were dependent on prednisone and calcineurin inhibitors found that rituximab significantly
reduced the relapse rate at 3 months (18.5% and 48.1% in the experimental and control arms, respectively), and it
also increased the likelihood of a child not requiring prednisone or calcineurin inhibitor treatment18. Many
studies have reported that rituximab treatment prolonged remission in patients with refractory NS19.

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The aim of this study was to combine the current evidence from all
eligible comparative studies to systematically evaluate the use of
rituximab versus current immunosuppressive agents in treating chil-
dren with refractory NS.

Methods
Literature search. This meta-analysis was conducted according to the Preferred
Reporting Items for Systematic Reviews and Meta-Analyses statement20. Our meta-
analysis searches were conducted using the PubMed, Web of Science Knowledge and
Cochrane Library databases from their inception dates to August 1, 2014. The search
applied the following search terms: ‘‘rituximab’’, ‘‘CD20’’, and ‘‘nephrotic syndrome’’.

Study selection criteria and study types. RCTs or comparative cohort studies that
evaluated the efficacy and safety of rituximab in treating pediatric patients with
refractory NS were included.

Type of participants. The patients were diagnosed with NS at 18 years of age and
younger.

Type of interventions. Rituximab and current immunotherapy were compared.

Different schedules and modalities of rituximab were included.

Analyzed outcomes. The primary outcome was relapse-free survival. The secondary
outcomes were (1) complete remission events, (2) biological indicators, including
Figure 1 | Flow chart of study selection.
proteinuria, serum albumin, serum cholesterol and serum creatinine, and (3) adverse
events.
study selection process is shown in Figure 1. The basic characteristics
Study selection and data extraction. The references obtained from the electronic of the included studies are listed in Table 1.
search were evaluated by two independent reviewers (Zhao Z and Liao G) using a
study selection form. The initial assessment was based on screening the titles and
abstracts; studies that did not meet the inclusion criteria were excluded. The studies
Assessing the quality of the studies. The risk of bias for each of the
that were not excluded after an initial evaluation were retrieved for full text screening included RCTs is shown in Table 2. The Newcastle-Ottawa scale
and, according to the inclusion criteria, it was determined whether the study should scores awarded 7 stars for a study reported by Sinha A28 and 5
be included in our analysis. In cases of disagreement, the final decision for inclusion stars for a study reported by Delbe-Bertin L29.
was made by consensus among the authors. Review articles, case reports, comments,
meeting abstracts and editorials were excluded.
The data were extracted by two independent reviewers (Zhao Z and Liao G). The
Efficacy of rituximab in children with nephrotic syndrome.
extraction data included the (1) study characteristics (authors, publication year), Relapse-free survival. One study27 reported that the median
(2) study design features, (3) study participants (e.g., eligibility criteria and baseline relapse-free survival rate favored the rituximab group over the
characteristics), (4) study interventions, and (5) study outcomes (efficacy and safety placebo group, with a statistically significant difference (HR 5
outcomes).
0.27; 95% CI, 0.14 to 0.53; P , 0.0001). In another study28, the
Bias and quality assessments of the included studies. The risk of bias in each
relapse-free survival rate was similar in the two groups (rituximab
included RCT was evaluated using the Cochrane Collaboration’s ‘Risk of bias’ tool21. versus tacrolimus) (P 5 0.86). The third study reported that three
The quality assessment of the comparative cohort studies was performed using the patients in each group achieved remission26. Ravani P18 reported
Newcastle-Ottawa scale (http://www.ohri.ca/programs/clinical_epidemiology/ that the drug-free rates at three months were 62.9% and 3.7%
oxford.asp), which included three main categories: (1) selection of cohort,
(2) comparability of cohort, and (3) determination of outcomes.
in the rituximab group and the other immunotherapy group,
respectively; we considered that these results could potentially
Statistical analysis. Our meta-analysis was performed using the RevMan software represent the relapse-free survival rate. The pooled HRs of the four
(version 5.20, The Nordic Cochrane Centre, Copenhagen, Denmark) and Stata included studies revealed a significant difference between the
software (version 11.0, Stata corporation, College Station, TX, USA). For relapse-free rituximab treatment group and the control therapy group (HR 5
survival, a hazard ratio (HR) and its 95% confidence interval (CI) were applied for
0.49, 95% CI, 0.26–0.92, P 5 0.03); a random-effect model was used
analysis. For dichotomous outcomes (adverse events and response rate), risk ratios
(RRs) were calculated, and these RRs were then pooled. Continuous variables were because of significant heterogeneity (I2 5 55%, P 5 0.08), and the
analyzed using mean differences (MDs) and 95% CIs. The heterogeneity of the results are outlined in Figure 2.
included studies was analyzed using the Cochrane Q test and the I2 statistic, and
P , 0.1 or I2 . 50% represented significant heterogeneity. If there was significant Complete remission rate. A complete remission rate was reported in
heterogeneity, we used a random effects model for the data analysis. Otherwise, we
used a fixed effect model.
three studies18,26,28. Pooled data from the three studies indicated that
rituximab treatment seemed to achieve a better complete remission
rate than other immunotherapy drugs (39.62% versus 25.45%) (RR:
Results 1.62, 95% CI: 0.92–2.84, P 5 0.09), as shown in Figure 3.
Our literature search identified 600 articles, of which 243 were from
PubMed, 349 from Web of Science, and 8 from the Cochrane Library. Biochemical indicators. Serum albumin. Two studies evaluated the
Using Endnote software, 190 repeated studies were removed. After serum albumin index after treatment26,28. Pooled analysis of the data
screening the titles and abstracts, 400 studies were excluded, and the revealed that there was no significant difference between the two
remaining 10 articles underwent full-text screening. Five studies groups (MD 5 0.18 g/dl, 95% CI 5 20.24 to 0.60 g/dl), with no
were excluded for the following reasons: two studies compared treat- heterogeneity among these studies (I2 5 0, P 5 0.53) (Figure 4A).
ment effects before and after using rituximab in the same series of
patients19,22; another study was a comparison of two groups that both Serum creatinine. Only two studies reported serum creatinine at the
used rituximab, with or without mycophenolate mofetil23; the other end of treatment26,28. Pooled data from the two included studies
two studies compared different doses of rituximab infusion24,25. suggested that there were no significant difference between the two
Finally, five studies were included for our analysis, three of which treatments (MD 5 0.01 mg/dl, 95% CI, 20.11 to 0.13, P 5 0.89).
were RCTs18,26,27; one study was a retrospective comparative control Moreover, there was no heterogeneity, and the analysis was
study28, and one was a prospective comparative control study29. The performed using a fixed effect model (I2 5 0, P 5 0.58) (Figure 4B).

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Table 1 | Basic characteristics of included studies

Follow-up
Study Year Country Study design Group Case Age Sex m/f Intervention time(M)
Delbe-Bertin L 2012 France single-center RTX 12 - 5/7 Treatment group 18M
Prospective control 16 7/9 . RTX(one to four infusions of
control 375 mg/m2)
comparative . hydrocortisone
. Cotrimoxazole
. prednisone 60 mg/m2 per day,
tapered over 2 months (In the
case of relapse during RTX
treatment)
control group
. orally (MMF, cyclosporine, or
tacrolimus)
Lijima K 2014 Japan multicentre, RTX 24 11.5(5.0) 18/6 Treatment group 12M
double-blind, control 24 13.6(6.9) 16/8 . RTX an intravenous dose of
RCT 375 mg/m2 (maximum
500 mg) once weekly for 4
weeks.
. Methylprednisolone
. Acetaminophen
. d-chlorpheniramine maleate
Control group
. prednisolone(60 mg/m2 orally
three times a day (maximum of
80 mg per day) for 4 weeks, and
then tapered over 6 weeks.
Magnasco A 2012 Italy Multicentre RTX 16 8.5(4.4) 10/6 Treatment group 18M
RCT control 15 7.3(3.7) 9/6 . RTX(two infusions of 375 mg/m2)
. prednisone,
. calcineurin
inhibitors(cyclosporine 1
tacrolimus)
. angiotensin-receptor blocker and
angiotensinconverting enzyme
inhibitors(if necessary)
control group
. prednisone,
. calcineurin
inhibitors(cyclosporine 1
tacrolimus)
. angiotensin-receptor blocker and
angiotensinconverting enzyme
inhibitors(if necessary)
Ravani P 2011 Italy Single-centre RTX 27 10.2(4.0) 24/3 Treatment group 12M
parallel RCT control 27 11.3(4.3) 19/8 . RTX (one or two infusion of
375 mg/m2)
. chlorfenamine maleate,
. methyl prednisolone
. paracetamol
. prednisone was tapered off by
0.3 mg/kg per week if
proteinuria was ,1 g/d.
. calcineurin
Control group
. prednisone and calcineurin
Inhibitors(tapered off by 0.3 mg/
kg per week if proteinuria was
,1 g/d.)

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Table 1 | Continued

Follow-up
Study Year Country Study design Group Case Age Sex m/f Intervention time(M)
Sinha A 2011 India Retrospective RTX 10 12.2(2.3) 8/2 Treatment group 12M
control control 13 12.3(3.0) 10/3 . RTX(two or three infusions of
comparative 375 mg/m2)
. tacrolimus (oral at a dose of 0.1–
0.2 mg/kg/day in two divided
doses for 12 months
. Prednisolone(1.5 mg/kg on
alternate days for 4 weeks, then
reduced by 0.25 mg/kg every
2–4 weeks)
control group
. tacrolimus (oral at a dose of 0.1–
0.2 mg/kg/day in two divided
doses for 12 months
. Prednisolone(1.5 mg/kg on
alternate days for 4 weeks, then
reduced by 0.25 mg/kg every
2–4 weeks)
RTX, rituximab; M, month. RCT, randomized controlled trial.

Proteinuria. Two studies reported proteinuria at the end of erular filtration rate between the two groups. The adverse effects were
treatment18,26. Compared with other immunotherapies, rituximab similar between the two arms, and no significance differences were
treatment reduced proteinuria by 0.25 g/d (MD 5 20.25, 95% CI observed.
5 20.29 to 20.21, P , 0.00001). The results are showed in Our study indicated that rituximab treatment demonstrated ben-
Figure 4C. efits in terms of relapse-free survival, which was consistent with
previous studies. Gulati et al. reported that rituximab treatment in
Other parameters. Sinha A reported that there was no between- patients with SRNS or SDNS that was refractory to standard therapy
group difference (2 groups) in the estimated glomerular filtration could sustain long-term relapse-free survival30. A study from China
rate at the 1-year follow-up28. Furthermore, another included study reported that rituximab treatment demonstrated a 91.67% effective
reported that rituximab did not decrease the IgG levels in patients rate22. A recent review revealed that rituximab treatment reduced the
with SDNS compared with the control treatment, but it prolonged number of relapses per year, with minimal change in disease and little
preexisting low IgG levels29. focal segmental glomerulosclerosis31. Tellier et al. reported that 4
(22%) of 18 patients with idiopathic NS who were treated with ritux-
Safety. Adverse events. It was reported that the adverse effects imab experienced remission without relapse, and the remaining
included bronchospasm, hypotension, and skin rash in patients patients had increased durations of remission32. In patients who
receiving rituximab treatment. Because of their minor severity, received one dose of rituximab (375 mg/m2), 25%–40% were in sus-
these adverse events rapidly and completely resolved by reducing tained remission at 12–17 months33,34. Sinha A indicated that therapy
the drug infusion rate or providing minor supportive treatment. with rituximab could reduce relapse rates in children with refractory
We only included grade 3–4 adverse events in the analysis. No NS35.
significant differences were observed in events of bronchospasm NS is characterized by a large amount of proteinuria. Reducing
(RR 5 5.84, 95% CI, 0.73 to 46.34, P 5 0.10), hypotension (RR 5 proteinuria is part of the treatment for NS. Kong et al. reported that
2.94, 95% CI, 0.48 to 18.07, P 5 0.24), acute renal failure (RR 5 0.97, approximately 90.1% of patients receiving rituximab treatment
95% CI 5 0.14 to 6.54, P 5 0.98), or skin rash (RR 5 2.91, 95% CI 5 achieved complete or partial remission of proteinuria36. Another
0.32 to 26.79, P 5 0.35) between the two groups. study reported that rituximab treatment could significantly reduce
24-hour proteinuria in patients with NS25. Indeed, the combined data
Publication bias. Relapse-free survival was assessed for publication indicated that rituximab treatment could reduce proteinuria.
bias. No evidence of publication bias was disclosed among the However, rituximab did not significantly increase serum albumin.
included studies by statistical testing, using Stata software, version This disparity might be attributed to the following causes. First, the
11.0 (Egg’s test, P 5 0.238; Begg’s test, P 5 0.734). patients who were included for analysis had different pathological
patterns and different treatment responses to rituximab, which
Discussion might have influenced the results. For example, the pathogenetic
Our meta-analysis included three RCTs and two comparative control differences between children who are resistant ab initio and those
studies involving 184 patients. There were 89 patients in the ritux- with delayed resistance would have resulted in different treatment
imab arm and 95 patients in the control arm. Our results indicated effects. The study reported by Magnasco A26 might have included
that rituximab treatment could significantly improve the relapse-free patients with different genetic backgrounds or sensitivities to ritux-
survival rate in patients with NS compared with control therapy. imab and, thus, might have indicated that rituximab might not be a
Moreover, rituximab treatment seemed to achieve a higher complete good choice in children who were unresponsive to steroids and cal-
remission rate (39.62% for rituximab versus 25.45% for the control). cineurin inhibitors, particularly for those unresponsive ab initio. By
Furthermore, rituximab treatment significantly reduced the incid- contrast, some case series have reported that rituximab might have a
ence of proteinuria. There were no significant differences in the good effect on NS who are unresponsive to prednisone and calci-
serum albumin and serum creatinine levels or the estimated glom- neurin inhibitors30,37. Second, the administration of rituximab dif-

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Table 2 | Risk of bias assessment for each included RCTs

Authors’
Bias judgement Support for judgement
Lijima K 2014
Random sequence generation Low risk Quote:‘‘We applied the minimisation method using a computer- generated
(selection bias) sequence (SAS PROC PLAN)’’
Allocation concealment (selection bias) Low risk Quote:‘‘Patients, patients’ guardians, caregivers, treating physicians,
and individuals assessing outcomes were masked to assignments’’.
Blinding of participants and personnel Low risk Quote:‘‘double blind’’. Comment: Probably done.
(performance bias)
Blinding of outcome assessment (detection bias) Low risk Obtained from medical records; reviewer authors do not believe this will introduce
bias.
Incomplete outcome data (attrition bias) Low risk All patients were included for analysis.
Selective reporting (reporting bias) Low risk Expected outcomes were reported.
Other bias Low risk The study with well-designed, double-blinded, and masking.
Magnasco A 2011
Random sequence generation unclear risk The study did not provide information about random sequence generation
(selection bias)
Allocation concealment (selection bias) High risk Quote: ‘‘open-label study’’
Blinding of participants and personnel High risk Quote: ‘‘open-label study’’
(performance bias)
Blinding of outcome assessment (detection bias) Low risk Obtained from medical records; reviewer authors do not believe this will introduce
bias.
Incomplete outcome data (attrition bias) Low risk One patient discontinued therapy in rituximab group, 1 discontinued therapy in control
group.
But all patients were included for analysis.
Selective reporting (reporting bias) Low risk All patients were included for analysis. Expected outcomes were reported.
Other bias Low risk The basic characteristics of patients were well matched, and delayed adverse effects
were observed.
Ravani P 2011
Random sequence generation Low risk Quote:‘‘Assignments followed permuted block randomization lists
(selection bias) (stratified by center and signs of toxicity) with blocks of variable size’’.
Allocation concealment (selection bias) Low risk Central allocation.
Blinding of participants and personnel Low risk Research facilitating follow-up data measurements were blinded to treatment group.
(performance bias)
Blinding of outcome assessment (detection bias) Low risk Primary outcome (% change in proteinuria) was measured in central laboratory.
Reviewer authors do not believe this will introduce bias.
Incomplete outcome data (attrition bias) Low risk All patients were included for analysis
Selective reporting (reporting bias) Low risk Expected outcomes were reported.
Other bias Low risk The study was supported by 5 non-pharmaceutical agencies and was a investigator-
driven study;

fers. Magnasco A26 adopted a treatment that consisted of two infu- power did not reach the level of statistical significance. If more cases
sions of rituximab, and two to three infusions of rituximab were used were analyzed (6 times more), rituximab would have had a positive
in the Sinha A28 study. A higher dose of rituximab could effectively effect. A systematic review reported that rituximab treatment signifi-
reduce proteinuria and increase serum albumin in refractory NS. cantly reduced proteinuria and increased serum albumin in idio-
Third, only two studies were included for the analysis of serum pathic NS31. As mentioned above, larger, well-designed,
albumin, and there was a small number of cases (26 in the rituximab prospective, controlled studies should be performed to assess these
group and 28 in the other immunotherapy group). Indeed, rituximab issues.
therapy reduced proteinuria with the amelioration of serum albu- Rituximab therapy was well tolerated in most patients. One review
min, as shown in Figure 4, and the mean serum albumin level in the reported that the most frequent adverse event was infusion-related
rituximab group was higher than that in the other immunotherapy reactions to rituximab therapy, which accounted for 22.4% of all
group (2.63 g/dl versus 2.53 g/dl in the Magnesco A study and 3.8 reported adverse events. The second most common adverse event
g/dl versus 3.4 g/dl in the Sinha A study). However, the statistical was acute reaction (22.2%). Other related adverse effects included

Figure 2 | Forest plot showing a meta-analysis for riruximab treatment group versus control treatment group on relapse-free survival.

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Figure 3 | Forest plot showing a meta-analysis for riruximab treatment group versus control treatment group on complete remission rate.

anaphylaxis, rash, bronchospasm, abdominal pain, vomiting, chills, decreased from 0.27 mg/kg to 0 mg/kg, and the median cumulative
and so on13. The study demonstrated that using a more targeted dose to achieve remission from relapse decreased from 19.5 mg/kg to
rituximab treatment did not significantly reduce the incidence of 0.5 mg/kg after rituximab treatment in patients with steroid-
adverse events. The following factors may explain the occurrence dependent or frequently relapsing idiopathic NS19. Some studies have
of these adverse events. Most of the adverse effects (e.g., hypotension, revealed that rituximab treatment significantly reduced steroid doses
bradycardia, chest tightness, and body ache) were infusion reactions compared with other immunotherapies19,27. Therefore, reducing the
due to non-humanized anti-CD20 antibodies (rituximab), and they steroid dose might prevent steroid-related side effects. Rituximab
usually occurred at the initial infusion. These adverse effects could be therapy resulted in the discontinuation of steroids for more than
well managed with premedication (with steroid and antihistamines) 200 days without relapses in more than half of the patients, and it
or by reducing the infusion rate or discontinuing the drug. Currently, seemed to improve the peak Z score27. Sato M reported that ritux-
humanized anti-CD20 antibodies (ofatumumab and obinutuzumab) imab treatment could improve the growth and obesity indices of
are under clinical investigation; whether these new agents could some children with SDNS who were suffering from the severe side
reduce the incidence of adverse events must be further evaluated. effects of steroids38.
However, rituximab did demonstrate some advantages over other In the studies included in this meta-analysis, the schedules and
immunotherapies. Rituximab therapy significantly reduced the use modalities of rituximab administration were not uniform. A single
of steroids and immunosuppressive agents. Ruggenenti et al. dose of 375 m/m2 rituximab accompanied by a B cell-driven infusion
reported that the median per-patient steroid maintenance dose protocol administered over 4 weeks constitutes the most commonly

Figure 4 | Forest plot showing a meta-analysis for riruximab treatment group versus control treatment group on A. serum albumin; B. serum
creatinine; C. proteinuria.

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applied regimen for NS in clinics. Other studies have used one, two or follow-up28; longer follow-up evaluations assessing renal function
three infusions. In clinical practice, a dose of intravenous corticos- outcomes were not available among the selected studies. Fourth,
teroid is often administered with an infusion of rituximab. The infu- due to limited information, the relapse rates were not evaluated in
sion of rituximab in combination with infused/oral corticosteroid our study. Fifth, the cost of rituximab treatment is high24; therefore,
drugs was reported in all included studies. In three studies27–29 not all the included studies evaluated the cost-effectiveness of ritux-
(Lijima K, Sinha A, and Delbe-Bertin L), the patients were treated imab in treating NS. It is essential to evaluate the cost-effectiveness of
30 minutes before the infusion of rituximab with corticosteroid ther- rituximab in treating NS. Sixth, the number of included cases was
apy. This additional dose of intravenous steroid could reduce the small. Future studies should address these issues.
adverse infusion effects resulting from rituximab and might yield In conclusion, rituximab can be considered an effective and safe
additional benefits. A study from the Rituximab in Nephrotic treatment option for SNNS and SDNS because it prolongs relapse-
Syndrome of Steroid-Dependent or Frequently Relapsing Minimal free survival, increases the complete remission rate, and reduces
Change Disease Or Focal Segmental Glomerulosclerosis (NEMO) proteinuria. However, the long-term effects and cost-effectiveness
Study Group reported that in a series of 30 patients with NS, 29 of rituximab treatment were not fully assessed. Additional studies
patients received an infusion of rituximab combined with corticos- with well-designed and longer follow-up periods are needed to
teroid; 28 patients experienced complete remission, and 2 patients address these issues.
achieved partial remission19. Additional studies are required to assess
the clinical benefits of a concurrent infusion of rituximab plus a
1. Certikova-Chabova, V. & Tesar, V. Recent insights into the pathogenesis of
steroid compared with an infusion of rituximab only. nephrotic syndrome. Minerva Med 104, 333–347 (2013).
A number of reports have reported using anti-CD20 antibodies 2. Eddy, A. A. & Symons, J. M. Nephrotic syndrome in childhood. Lancet 362,
(rituximab) in children with NS. From the literature, we might specu- 629–639 (2003).
late that the effects of rituximab are better in SDNS and frequent- 3. McKinney, P. A., Feltbower, R. G., Brocklebank, J. T. & Fitzpatrick, M. M. Time
trends and ethnic patterns of childhood nephrotic syndrome in Yorkshire, UK.
relapse NS than in SRNS6,17,22,27,30,35,39. In a systematic review that Pediatr Nephrol 16, 1040–1044 (2001).
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The use of rituximab in SRNS occurs under the following circum- nephrotic syndrome: new guidelines from KDIGO. Pediatr Nephrol 28, 415–426
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stances. First, rituximab could play a role in SRNS by maintaining 7. Pravitsitthikul, N., Willis, N. S., Hodson, E. M. & Craig, J. C. Non-corticosteroid
remission and reducing the dose of steroids and other immunosup- immunosuppressive medications for steroid-sensitive nephrotic syndrome in
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idiopathic focal segmental glomerulosclerosis. Pediatr Nephrol 22, 215–221
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pressants, treatment with rituximab might yield encouraging 9. Prasad, N., Gulati, S., Sharma, R. K., Singh, U. & Ahmed, M. Pulse
results13. cyclophosphamide therapy in steroid-dependent nephrotic syndrome. Pediatr
However, it is challenging to treat patients with SRNS who resist- Nephrol 19, 494–498 (2004).
10. Ueda, N. et al. Beneficial effect of chlorambucil in steroid-dependent and
ant to rituximab. New anti-CD20 monoclonal antibodies have been
cyclophosphamide-resistant minimal change nephrotic syndrome. J Nephrol 22,
utilized in clinics. Ofatumumab and obinutuzumab were both 610–615 (2009).
approved to treat chronic lymphocytic leukemia(CLL)40. Unlike chi- 11. Gellermann, J., Ehrich, J. H. & Querfeld, U. Sequential maintenance therapy with
meric rituximab, both of these monoclonal antibodies are huma- cyclosporin A and mycophenolate mofetil for sustained remission of childhood
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idiopathic nephrotic syndrome. Pediatr Nephrol 28, 911–918 (2013). Z.Z., G.L. and H.Z. conducted the literature search, determined studies for exclusion and
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34. Fujinaga, S. et al. Single infusion of rituximab for persistent steroid-dependent manuscript, read and approved the final manuscript. All authors reviewed the paper and
minimal-change nephrotic syndrome after long-term cyclosporine. Pediatr approved the final manuscript.
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Additional information
Competing financial interests: The authors declare no competing financial interests.
gfu267 (2014).
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for adult-onset primary glomerulonephritis and review of literature. Int Urol of rituximab in treating childhood refractory nephrotic syndrome: A meta-analysis. Sci.
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23, 1269–1279 (2008). NoDerivs 4.0 International License. The images or other third party material in
38. Sato, M., Ito, S., Ogura, M. & Kamei, K. Impact of rituximab on height and weight this article are included in the article’s Creative Commons license, unless indicated
in children with refractory steroid-dependent nephrotic syndrome. Pediatr otherwise in the credit line; if the material is not included under the Creative
Nephrol 29, 1373–1379 (2014). Commons license, users will need to obtain permission from the license holder
39. Prytula, A. et al. Rituximab in refractory nephrotic syndrome. Pediatr Nephrol 25, in order to reproduce the material. To view a copy of this license, visit http://
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