Efficacy and Safety of rituximab in children with difficult-to-treat nephrotic syndrome ; a systematic review

1Department of Pediatrics, Mashhad University of Medical Sciences, Mashhad, Iran 2Clinical Research Unit, Mashhad University of Medical Sciences, Mashhad, Iran 3Department of Community Medicine, Mashhad Branch, Islamic Azad University, Mashhad, Iran 4Department of Acupuncture, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran 5Department of Pediatrics, Mashhad Medical Sciences Branch, Islamic Azad University, Mashhad, Iran 6Valiasr Hospital, Imam Khomeini Complex, Tehran University of Medical Sciences, Tehran, Iran http://journalrip.com


Introduction
Nephrotic syndrome (NS) is a complication diagnosed by heavy proteinuria, hypoalbuminemia (serum albumin <2.5 g/dL), often associated with hypercoagulability and dyslipidemia.According to the NS clinical guidelines, for the management of children who develop frequentlyrelapsing NS (FRNS) or steroid-dependent NS (SDNS), a low-dose alternate day steroid regimen, as the first-line treatment, is prescribed (1).Long-term glucocorticoid use in FRNS/SDNS patients leads to reduced bone mineral density, hypertension, increased infection risks, comorbidities such as cushingoid habitus, growth retardation, striae and acne, cataracts, pseudotumor cerebri, impaired glucose tolerance and hypercholesterolemia (2).Approximately 20% of children do not respond completely and have steroid-resistant NS (SRNS), and 80%-90% of children with steroid-sensitive NS (SSNS) experience relapses.Among these relapsing children, 50% develop DOI: 10.15171/jrip.2018.67SDNS (3).Refractory nephrotic refers to patients with FRNS, SDNS, and SRNS which are difficult to be controlled by variable immunosuppressants (4).Rituximab (RTX) might be a hopeful treatment for refractory NS in children, but the long-term effects and cost-effectiveness of RTX treatment have not been fully assessed (3).Several studies have suggested RTX as a proper drug for the treatment of children with FRNS/SDNS (5)(6)(7)(8).This study aims to have a systematic review to identify the efficacy and safety of RTX in children with difficult-to-treat NS.

Methods
We searched Embase, DOAJ (Directory of open access journals), PubMed, the Cochrane Library, Science Direct, Scopus, and Web of Science (updated up to July 2017).Search term was ("nephrotic syndrome" or "minimal change disease" or "focal segmental glomerulosclerosis" or membranous) and (''rituximab'' or ''CD20'').We scanned bibliographies in relevant papers and conference proceedings.Studies by the same author were checked for possible overlapping participant groups.If the study was reported as duplicate, only the most recent or complete study was comprised.The following selection criteria were applied; we included all randomized trials and observational studies about using RTX in children with difficult-to-treat NS.

Data extraction and quality assessment
Two independent reviewers extracted data from the papers according to the selection criteria.Disagreements were resolved by discussion between two reviewers considering the opinion of a third reviewer.The following information was abstracted from each contained investigation; first author and year of publication, design of investigation, sample size, mean age of individuals, intervention regime, follow-up duration, and outcome measures for each group.All the analysis were based on previously published investigations.Hence, no ethical approval or patient consent was required.

Search results and characteristics
The literature search and reference mining yielded 919 potential relevant papers.We removed 340 papers because of duplicate publication.We also excluded 513 papers after reviewing the titles and abstracts while they were books, book sections, and review papers.Thus, they were not relevant.Then, we reviewed full-text of selected articles and removed 49 studies because the topics were not relevant to the subject.Finally, 17 investigations were included in the systematic review (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20).The flow diagram of study selection is shown in Figure 1.Characteristics and the details of the studies are illustrated in Table 1.

Outcome
The summary of outcomes of our study is provided in Table 2. Efficacy of RTX in children with NS in most of the studies was assessed with relapse-free survival or complete remission rates.In a study (5), reduction of median yearly number of relapses with use of RTX was reported (5).Some of the studies reported biochemical indicators such as proteinuria (14).

Discussion
Almost all studies showed that RTX was effective in the treatment of refractory NS in children, and it could Azarfar et al hypercholesterolemia (2).Approximately 20% of children do not respond completely and have steroid-resistant NS (SRNS), and 80%-90% of children with steroidsensitive nephrotic syndrome (SSNS) experience relapses.Among these relapsing children, 50% develop SDNS (3).Refractory nephrotic refers to patients with FRNS, SDNS, and SRNS which are difficult to be controlled by variable immunosuppressants (4).Rituximab (RTX) might be a hopeful treatment for refractory NS in children, but the long-term effects and cost-effectiveness of RTX treatment have not been fully assessed (3).Several studies have suggested RTX as a proper drug for the treatment of children with FRNS/SDNS (5)(6)(7)(8).This study aims to perform a systematic review to identify the efficacy and safety of RTX in children with difficult-to-treat NS.

Methods
We searched, Embase, DOAJ (Directory of open access journals), PubMed, the Cochrane Library, Science Direct, Scopus, and Web of Science (updated up to July 2017).The search term was ("nephrotic syndrome" or "minimal change disease" or "focal segmental glomerulosclerosis" or membranous) and (''rituximab'' or ''CD20'').We scanned bibliographies in relevant papers and conference proceedings.Studies by the same author were checked for possible overlapping participant groups.If the study was reported as duplicate, only the most recent or complete study was comprised.The following selection criteria were applied; we included all randomized trials and observational studies about using RTX in children with difficult-to-treat NS.

Data extraction and quality assessment
Two independent reviewers extracted data from the papers according to the selection criteria.Disagreements were resolved by discussion between two reviewers considering the opinion of a third reviewer.The following information was abstracted from each contained investigation; first author and year of publication, design of investigation, sample size, mean age of individuals, intervention regime, follow-up duration, and outcome measures for each group.All the analysis were based on previously published investigations.Hence, no ethical approval or patient consent was required.

Search results and characteristics
The literature search and reference mining yielded 919 potential relevant papers.We removed 340 papers because of duplicate publication.We also excluded 513 papers after reviewing the titles and abstracts while they were books, book sections, and review papers.Thus, they were not relevant.Then, we reviewed full-text of selected articles and removed 49 studies because the topics were not relevant to the subject.Finally, 17 investigations were included in the systematic review (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20).The flowchart of study selection is shown in Figure 1.Characteristics and the details of the studies are illustrated in Table 1.

Outcome
The summary of outcomes of our study is provided in Table 2. Efficacy of RTX in children with NS in most of the studies was assessed with relapse-free survival or complete    Severe recurrent bacterial infections = 1 Acute lung injury = 1

Rituximab in children with nephrotic syndrome
The anti-CD20 monoclonal antibody may not be effective in all pediatric patients with rapid post-transplant recurrence of NS.The ratio of benefit to risk should precisely be balanced decrease the use of immunosuppressants and steroid.Only one study concluded that RTX might not be effective in all pediatric cases of rapid post-transplant recurrence of NS, and they suggested that before deciding to use this protocol, the ratio of benefit to risk should carefully be balanced on an individual basis (10).In this systematic review, 17 studied were included, but only two of them were randomized clinical trials (most of them were retrospective studies without control groups), hence we could not do a quantitative synthesis (metaanalysis).In recent year, some review articles have been published on use of RTX in treating childhood NS.The results of a review article regarding efficacy and safety of RTX in treating childhood NS were similar to our results.That study concluded significant gradual benefits for the treatment of NS by adding RTX to corticosteroid and/or calcineurin inhibitors.In safety data they collected, RTX has a limited number of adverse effects; they showed that the most common of them occurred during the infusions, but that study included only randomized control trials and is thus different from our study (1).In our investigation, some studies such as (19) clearly explained the side effects of RTX (19).Another meta-analysis study showed that for childhood refractory NS, RTX might be a promising treatment (3).They showed that RTX also made a higher rate of complete remission, and reduced the proteinuria in patients, but they expressed that the long-time effects and cost-effectiveness of RTX treatment were not fully determined.They suggested additional studies to address these issues (3).They included only four studies in their meta-analysis.One of their studied sources was done only in adults (contrary to our studies) in which the authors systematically summarized and analyzed data from preexisting studies reporting the outcome of RTX (RTX) treatment in relapsing minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS).They concluded that in frequently relapsing and SDNS due to MCD and FSGS, RTX is effective in reducing the proportion of relapses and sparing immunosuppression.They showed that during treatment with RTX, proteinuria decreased from 2.43 (0-15) g/d to 0 (0-4.89)g/d (P < 0.001), while serum albumin increased from 2.9 (1.2-4.6) at baseline to 4.0 (1.8-5.09)g/L (P = 0.001), but in most of children studies we reviewed, similar data had not been reported.In the review article of ( 21), the authors suggested confirmation of their finding by further controlled and prospective studies (21).

Figure 1 .
Figure 1.Flow-chart of study selection process.

Figure 1 .
Figure 1.Flow-chart of study selection process.

Table 1 .
General characteristics of trials included in this systematic review

Table 2 .
Outcome of studies

Table 2 .
Focal segmental glomerulosclerosis, SDNS: Steroid-dependent nephrotic syndrome, FRSDNS: Frequent relapses or steroid dependence nephritic syndrome, FRNS: Frequently relapsing nephrotic syndrome (More than one relapses of nephrotic syndrome within size months following the initial remission, or more than three relapses within any 12-month period), SRNS: Steroid-resistant nephrotic syndrome Continued