Pediatric Nephrology (2021) 36:1397–1405

https://doi.org/10.1007/s00467-020-04609-0

EDUCATIONAL REVIEW

Rituximab in children with steroid sensitive nephrotic syndrome:

in quest of the optimal regimen
Eugene Yu-hin Chan 1,2 & Kjell Tullus 1

Received: 7 April 2020 / Revised: 2 May 2020 / Accepted: 11 May 2020 / Published online: 24 June 2020
# IPNA 2020

Abstract
Rituximab has emerged as an effective and important therapy in children with complicated frequently relapsing and steroid-
dependent nephrotic syndrome to induce long-term disease remission and avoid steroid toxicities. The optimal rituximab regimen
is not totally well defined, and there are many varying practices worldwide. We will in this review describe how patient factors,
rituximab dose, and use of maintenance immunosuppression affect treatment outcomes. Specifically, low-dose rituximab without
concomitant immunosuppression is associated with shorter relapse-free duration while other regimens have comparable out-
comes. Patients with more severe disease generally have worse response to rituximab. Although rituximab appears to be
generally safe, there are growing concerns of chronic hypogammaglobulinemia and impaired immunity especially in young
children. Reliable prognostications and biomarkers for guiding subsequent treatments to avoid excessive treatments are yet to be
identified. In this review, we will outline the, as we see it, best approach of rituximab in childhood steroid sensitive nephrotic
syndrome at the present state of knowledge.

Keywords Rituximab . Nephrotic syndrome . Steroid-dependent nephrotic syndrome . Children . Steroid-sensitive nephrotic
syndrome . Biologics

Introduction relapse despite multiple immunosuppressive therapies and

are classified as complicated FRSDNS [3]. These children
Idiopathic nephrotic syndrome (NS) is an uncommon child- are often multi-drug dependent and are at high risk of devel-
hood disease characterized by nephrotic-range proteinuria, oping significant toxicities from steroids and other immuno-
edema, and hypoalbuminemia. The reported incidence of NS suppressive agents, such as short stature, cosmetic changes,
depends on ethnicity or country of origin and has considerable Cushing syndrome, infection, and nephrotoxicity.
variation, ranging from 1.15 to 16.9 per 100,000 persons [1]. Rituximab, a chimeric anti-CD20 monoclonal antibody,
Although the majority of these children respond to steroid was originally used to treat B-cell non-Hodgkin’s lymphoma
therapy, 50% patients develop frequent relapses (FR) and/ or at a dose of 375 mg/m2 for four infusions. It did then become
steroid dependency (SD) [2]. A range of immunosuppressants used in different autoimmune diseases like systemic lupus
including levamisole, cyclophosphamide, calcineurin inhibi- erythematosus, and in those cases rituximab was mostly pre-
tor (CNI), and mycophenolate mofetil (MMF) are often used scribed in the dose of 750 mg/m2 for two infusions. Rituximab
to minimize the steroid burden for children with FRSDNS. was first described to induce remission of SDNS in a 16-year-
However, overall 20–30% children with NS continue to old boy who was treated for autoimmune thrombocytopenic
purpura [4]. Since then, three randomized control trials have
confirmed the efficacy of rituximab in complicated FRSDNS
* Eugene Yu-hin Chan [5–7]. Recently, rituximab is also found to be effective in
[email protected] children as first-line steroid-sparing agent [8]. Rituximab does
in most cases lead to a sustained relapse-free period with re-
1
Department of Paediatric Nephrology, Great Ormond Street Hospital
duction or even discontinuation of immunosuppression, espe-
for Children NHS Trust, London, UK cially corticosteroids.
2
Paediatric Nephrology Centre, Hong Kong Children’s Hospital,
Nonetheless, there are substantial variations in rituximab
Kowloon, Hong Kong prescription worldwide, ranging from 375 to 1500 mg/m2
1398 Pediatr Nephrol (2021) 36:1397–1405

per treatment course [9, 10]. Use of maintenance immunosup- remission after rituximab [11, 14]. Number of relapses often
pression to extend disease remission is also a practice that is become fewer and less difficult-to-control with age towards
used by some centers [11–15]. Importantly, most patients adolescence. Younger age at rituximab initiation was associ-
(80%) eventually relapse, showing that the drug effect is not ated with earlier B cell reconstitution and potentially increased
permanent [16]. Repeated treatments are often required. The relapse risk [17, 18], although an earlier report did not support
rituximab-related safety profile is hence of crucial consider- this observation [15]. Several authors have not been able to
ation when clinicians decide on repeating therapies. identify underlying histology as a significant predictive factor
In this review, we will focus on children with steroid- of treatment response [7, 11, 14]. There is great variability in
sensitive nephrotic syndrome, notably complicated outcomes in different studies suggesting varying steroid re-
FRSDNS. We will discuss the evidence related to dosing reg- sponsiveness by ethnicity and country of origin. It ranges from
imen and adverse events of rituximab, in order to suggest the 69% in Pakistani to 98% in South Asians residing in Canada
optimal regimen and the re-treatment approach. [1]. However, an ethnic effect on the response to rituximab
would need to be confirmed in a larger scale, multi-ethnic
study.
Factors determining treatment response
Rituximab dose
The treatment outcomes following rituximab are determined
by patient factors, rituximab dose, and the use of maintenance
The rituximab dose used for childhood NS was initially
immunosuppression and are summarized in Fig. 1.
adopted from two previously used schedules. Some pe-
diatric nephrologists adopted the original prescription for
Patient factors treatment of lymphoma: four infusions of 375 mg/m2 at
1-week interval. Others used the schedule often applied
The clinical course in children with complicated FRSDNS is in autoimmune diseases such as lupus: two doses of 750
quite heterogeneous. Multiple patient factors account for a mg/m2, 2 weeks apart. Both regimens consist of a total
diverse response to rituximab. Notably, patients with a more dose of 1500 mg/m2. In recent years, a lower rituximab
severe disease are associated with worse response to rituxi- dose has been advocated with a potential benefit of lim-
mab. Iijima et al. reported a lower 1-year relapse-free survival iting cost and side effects [6, 19]. Only a few studies
in children with complicated FRSDNS [5], compared to those have to-date compared the efficacy of various rituximab
reported by Basu et al. who received rituximab as first-line regimens. Most of these reports were limited by their
agent for an uncomplicated disease (37% vs. 90%) [8]. retrospective nature, a small patient number, and failure
Children with a history of initial steroid resistance are often to separate the dose effect from the use of concomitant
multi-drug dependent and at risk of more relapses and shorter immunosuppression.
Factors associated with worse outcomes
• Severe disease (e.g. SRNS, complicated FRSDNS)
• Younger age at rituximab
• Higher number of prior IS
• ? Ethnicity

Paent
factors

Dose
• Significant interacon between dose & IS
• Low dose alone worse outcomes
• IS improves efficacy, especially with low-dose Treatment
• Other regimens comparable efficacy Outcomes
• Choice of maintenance IS - ? MMF
IS

Fig. 1 Factors affecting treatment outcomes of rituximab therapy. Patient frequently relapsing and/or steroid-dependent nephrotic syndrome; IS,
factors, rituximab dose, and concomitant immunosuppression interact immunosuppression; MMF, mycophenolate mofetil; SRNS, steroid
with each other and impact on treatment outcomes. FRSDNS, resistant nephrotic syndrome
Pediatr Nephrol (2021) 36:1397–1405 1399

Subgroup analyses from earlier retrospective observational An international, multicenter study on rituximab
studies suggested that patients receiving high-dose rituximab regimen
(1125–1500 mg/m2) had a longer remission period [15, 20].
Kemper et al. found the time to first relapse was 10.3 ± 3.5 Recently, we conducted an international, multicenter, retro-
months and 23.3 ± 18.7 months in children receiving rituxi- spective cohort study where 511 multi-ethnic children with
mab at 375–750 mg/m2 and 1125–1500 mg/m2, respectively complicated FRSDNS were recruited from 11 tertiary pediat-
(p < 0.05) [15]. Previous work by Webb et al. also found a ric nephrology centers in Asia, Europe, and North America
shorter median time to relapse in patients receiving one infu- [16]. All patients were steroid-sensitive and in remission at
sion of 750 mg/m2 compared to two infusions (5 vs. 16 first rituximab treatment, with a mean follow-up duration of
months; p = 0.03) [20]. 4.3 years. Six combinations of rituximab regimens were com-
Hogan et al. retrospectively examined the effect of rituxi- pared: low dose (375 mg/m2), medium dose (750 mg/m2), and
mab at dosing levels of 100 mg/m2, 375 mg/m2, and 750 mg/ high dose (1125–1500 mg/m2) per course, with or without
m2 in 61 children with SDNS, with 1-year relapse-free surviv- maintenance immunosuppression (defined as corticosteroid,
al rates being 50, 59, and 72%, respectively [18]. The risks of MMF, and/or CNI for more than 6 months).
B cell reconstitution and relapse were significantly increased Following rituximab, 80% children relapsed with a median
only in the very low-dose group of 100 mg/m2. Data on con- relapse-free period of 12.5 months. Both rituximab dose and
current immunosuppression was limited in that study. use of maintenance immunosuppression showed significant
Maxted et al. evaluated 60 UK children with FRSDNS in a interaction on treatment outcomes. Specifically, the relapse-
multicenter retrospective cohort study [21]. The author found free survival was not different in five of the six treatment
no statistical difference in the event-free survival at 12 months groups (10.9–14 months), while children who received the
between different rituximab regimens (375–1500 mg/m2), and lowest dose rituximab (375 mg/m2) without concomitant im-
suggested that low-dose rituximab at 375 mg/m2 was no less munosuppressive therapy had a shorter relapse-free survival
effective than higher dosing ranges. However, the dose distri- of 8.5 months. Results of the Kaplan-Meier analysis of various
bution was grossly uneven within the cohort and only five out regimens are presented in Fig. 2. Our unpublished data also
of 60 patients received rituximab at an intermediate dose showed that dosing schedule per se did not affect treatment
(750–1000 mg/m2). efficacy. For instance, children receiving a total dose of 750
mg/m2, either by a single infusion or 375 mg/m2 for two
infusions, had similar outcomes.
Maintenance immunosuppression In line with aforementioned patient factors, each 1-year
younger in age at first rituximab and one additional number
Concomitant immunosuppression has been proposed to ex- of prior immunosuppression increased relapse risk by 5% and
tend remission without prolonging B cell depletion [11, 12]. 19%, respectively. Ethnicity did not appear to affect treatment
This approach may be particularly valuable when using low- response in this well-defined patient population with compa-
dose rituximab and in children who run a complicated clinical rable disease severity. Renal histology was not analyzed in the
course [12, 14, 22]. Sinha et al. described higher rates of multivariate analysis, because up to 40% children in the cohort
sustained remission with pre-emptive mycophenolate mofetil did not receive a kidney biopsy. Important data pertaining to B
(MMF) if the patients were CNI-dependent, but not in those cell population and adverse events were inadequate due to
with uncomplicated SDNS [14]. Basu et al. also concluded different monitoring protocol and reporting bias.
that a higher proportion of children with refractory SRNS
sustained remission with post-rituximab MMF therapy [22]. Safety and long-term consequence
Although MMF appears to be a promising option [13], its
effect is not confirmed in some reports and thus the drug of It is crucial to understand the safety of rituximab and its long-
choice remains controversial [11, 17]. CNI may be more ef- term consequences in order to decide on the optimal treatment
fective than MMF in maintaining remission [23], but it is approach. Whether adverse events are dose- or time-
associated with nephrotoxicity after protracted use. A multi- dependent is still poorly studied and remains inconclusive.
center prospective randomized controlled trial is being con- Existing data however do not suggest that higher rituximab
ducted in Japan to examine the role of MMF as maintenance dose or increasing treatment courses lead to more side effects,
therapy following rituximab [24]. Currently, a randomized but these have to be interpreted carefully [16, 25, 26].
controlled trial from India, the RITURNS II study, is under- Overall, rituximab appears to be safe in children [5, 7–9,
way to determine the efficacy of maintenance MMF versus 15, 20, 25, 27, 28]. Infusion reactions are the most prevalent
repeating rituximab after initial course among children with adverse events. They are often self-limiting with pre-
SDNS (RITURNS II, Clinical Trials Registry Identifier: medications and reduction of speed of the infusion [16, 28].
NCT03899103). Serious complications do, however, occur occasionally,
1400 Pediatr Nephrol (2021) 36:1397–1405

Dose + Low + Medium + High

Without mIS With mIS

100 100

++
+
Relapse−free survival probability (%)

+
+
75
+ 75 +
++
+ +

+ +
50 + 50
+
+ +
++
++ +
+ ++
+
++ ++
++++++ + + + +++
25 + + + ++ 25
+ ++++
++++ +++ + + + ++++++ + ++ + +
++ + + +
+ + +
+ + + +++
p = 0.025 p = 0.167 +
0 0

0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8
Time (year)
Number at risk
Without mIS With mIS

−
−
46 15 4 3 3 1 0 0 0
−
−
145 74 36 17 9 6 4 3 0
Dose

117 60 30 15 10 7 3 2 0 91 39 16 5 1 0 0 0 0

− 65 39 14
0 1 2
7
3
3
4
3
5
2
6
0
7
0
8
− 47 24 11
0 1 2
8
3
4
4
4
5
2
6
1
7
0
8
Time (year)
Fig. 2 Relapse-free survival following different rituximab regimens. course of rituximab therapy at different dosing levels (low, 375 mg/m2;
(Reprinted from Chan et al. [16], with permission from Elsevier). medium, 750 mg/m2; high, 1125–1500 mg/m2) and stratified by the use
Kaplan-Meier curves for the relapse-free survival following the first of maintenance immunosuppression (mIS)

including rituximab-associated lung injury, fatal hepatitis re- Two important long-term sequelae after rituximab ther-
activation, and multifocal leukoencephalopathy [29–32]. apy warrant attention: its impact on a developing immu-
There are reports of severe infections such as fulminant viral nological system and persistent hypogammaglobulinemia.
myocarditis and atypical Pneumocystis jiroveci pneumonia Colucci et al. examined the lymphocyte populations and
[33, 34]. Although there is currently no consensus regarding vaccine competency in 27 children with FRSDNS who
Pneumocystis jiroveci prophylaxis in children with nephrotic were followed for more than 4 years after the first and
syndrome, co-trimoxazole is still recommended by some pe- at least 2 years after the last anti-CD20 infusion [39].
diatric nephrologists for 6 months following rituximab. Of Total memory and switched memory B cells were persis-
note, Kamei et al. found agranulocytosis (absolute neutrophil tently and significantly reduced in about 75% patients at
count of < 500mm3) in 9.6% patients at a median of 66 days last follow-up compared to baseline. The clinical signifi-
after rituximab, and it was more prevalent in young children cance of this is unknown. Antibodies against HBV and
[35]. These children often developed febrile illness and re- tetanus were reduced, indicating impaired vaccine compe-
quired interventions such as antibiotics and granulocyte tence. Eleven patients developed persistent
colony-stimulating factor [35]. There are to our knowledge hypogammaglobulinemia at last follow-up, and in four
no data on an increased chance for malignancies, if any, in children, the IgG levels were extremely low (less than
this patient population [36–38]. 160 mg/dL).
Pediatr Nephrol (2021) 36:1397–1405 1401

Parmentier et al. also described that 25 out of 86 children whether a novel approach of adding monthly IVIG for 5
developed hypogammaglobulinemia, and in 13 patients the months to low-dose rituximab can improve remission rates
low immunoglobulin level persisted beyond 1 year after B cell in SDNS (RITUXIVIG, Clinical Trials Registry Identifier:
recovery [26]. The development of this complication was not NCT03560011).
related to cumulative rituximab dose. About a third of patients The second way to do it is to monitor the B cell response
had concomitant infection, and one patient was complicated and to repeat rituximab when they repopulate. The third way
by enterovirus-associated fulminant myocarditis leading to is scheduled therapy to induce persistent B cell depletion.
heart transplantation [26, 33]. All these infected children were Despite growing evidence on various re-dosing strategies,
supplemented by intravenous immunoglobulin (IVIG) infu- the optimal approach remains controversial and requires a
sions. Of note, in both reports, younger age at time of first careful consideration between long-term efficacy and safety
anti-CD20 treatments was identified to be a significant risk profile.
factor for hypogammaglobulinemia (OR 2.14/year, p =
0.006) [26, 39]. This highlights the importance of monitoring Retreatment after B cell reconstitution
immunoglobulin levels and perhaps also vaccine antibody ti-
tres. Published guideline does not recommend an absolute Several reports showed that relapses occurred after B cell re-
level of IgG where immunoglobulin replacement therapy constitution [8, 17, 18, 43]. For this reason, B cell population
should be commenced [40]. The decision to substitute is the most frequently monitored biomarker, and its recovery
hypogammaglobulinemia should be based on degree of is an indication for re-treatment in some protocols [16, 43, 44].
hypogammaglobulinemia, nature of the infections (serious, In one study involving 18 children with SDNS, Kim et al.
persistent, unusual, or recurrent), vaccine competency, and repeated rituximab according to B cell reconstitution in 70%
response to antibiotic prophylaxis [40]. Further work is re- of all treatment cycles. Each patient received an average of 5.2
quired to clarify the management in asymptomatic, numerical ± 2.3 rituximab courses over a relatively short period of 2.8 ±
hypogammaglobulinemia. 1.1 years. Eight patients had sustained remission, and in 10
Although rituximab appears to be safe in a majority of patients, relapse rates reduced from 2.8 ± 1.5 to 1.3 ± 0.8
treated children, it is important to note that most data on safety relapses per year.
come from older children. More data are needed in young Delbet et al. compared B cell depletion duration of individ-
patients as this patient population is more likely to require ual patients between initial and subsequent rituximab treat-
multiple rituximab treatments, and they might also have a ments in 22 children with NS [45]. About 90% patients had
higher chance of neutropenia and hypogammaglobulinemia. a similar B cell depletion duration during subsequent treat-
ments. Individualized monitoring and even pre-emptive ritux-
Approach to maintaining remission and subsequent imab administration are therefore feasible, once the time to B
treatments cell repletion is determined for each patient.
Nonetheless, discrepancies concerning the temporal rela-
A significant proportion of patients with FRSDNS relapse 1 tionship between relapse and B cell population were frequent-
year after rituximab [16, 41]. Some of these children may ly observed in the literatures. For example, following B cells
develop frequent relapses or steroid dependence again, and recovery at a median of 160 days post-rituximab, Kamei et al.
if so require re-initiation of intensive immunosuppression found that only 73% of the 81 children with SDNS relapsed at
and additional rituximab [41]. Several policies in redoing ri- a median of 309 days [11]. On the other hand, Sato et al.
tuximab have been described to maintain long-term remission. described six out of 82 patients (7.2%) relapsed even in the
The most common is re-treatment after a relapse. This is the presence of B cell depletion after rituximab [46]. These pa-
indication for repeating rituximab in up to 87% of children tients had poor response to rituximab and developed repeated
with complicated FRSDNS [16]. As discussed, maintenance relapses during B cell depletion despite multiple treatment
immunosuppression may be a useful option to extend remis- courses and concomitant immunosuppression [46]. The above
sion, especially with low-dose rituximab [16]. In a follow-up findings indicate B cell reconstitution is not a reliable bio-
work of the RITURNS study which studied children without marker, and the timing of relapse can be considerably variable
previous immunosuppression for their FRSDNS, preliminary and much delayed. A complex interplay between immunity,
results showed that all children relapsed within 6 to 24 months circulating factors, and podocyte probably accounts for this
following initial course of rituximab as first-line therapy [42]. phenomenon [47].
Patients receiving MMF as co-therapy after second course of Not all B cell subsets are equally relevant in the pathogen-
rituximab had a longer remission than those who received esis of steroid-sensitive nephrotic syndrome [48]. Colucci
rituximab alone (80% relapse-free survival, 84 vs. 30 weeks), et al. conducted an interesting study on B cell subpopulations
and 75% patients remained relapse-free at 2 years. In France, a following rituximab in 28 children with FRSDNS [49]. While
randomized controlled trial is currently underway to examine total B cells reconstituted at a median of 6 months, there was a
1402 Pediatr Nephrol (2021) 36:1397–1405

sequential re-emergence of transitional, mature, and finally has been associated with encouraging results. However, until
memory B cells. Of note, only 4 patients (15%) relapsed at 9 long-term safety of this approach is established, we do have
months even when all B cell subsets recovered in most pa- concern to recommend a liberal use due to potential severe
tients, and only 14 children (50%) eventually relapsed at 24 complications.
months. The correlation between relapse and B cell population In our setting where treatment is subsidized, we now pre-
is thus not substantial. Of all subsets, only reconstitution of scribe rituximab at a single infusion of 750 mg/m2 (maximum
switched memory B cell (> 0.067% of total lymphocytes), a 1000 mg) without maintenance therapy to attain similar effi-
subcategory of memory B cells producing IgG, IgA, or IgE cacy and avoid protracted immunosuppression use. Since
antibodies, was predictive of a relapse upon multivariate anal- about 10% patients may develop an early relapse within first
ysis. Until evaluation of this particular subpopulation becomes month post-rituximab [5], we taper and discontinue the immu-
widely available, the utility of routine B cell monitoring in nosuppressants gradually over 1 to 2 months following ritux-
guiding re-treatment may be limited. imab. In our experience, most of these children achieve long-
Repeating rituximab based on B cell reconstitution may term remission subsequently once rituximab comes into full
lead to sustained remission and avoid steroid use related to effect.
relapses. However, a significant proportion of patients may be Alternatively, low-dose rituximab (375 mg/m2) with co-
subjected to excessive or unnecessarily early treatments with medication such as MMF is an attractive approach to prolong
long-term safety concerns. Further investigations are required remission, reduce cost, and limit potential rituximab adverse
to delineate the relationship between B cell population and events, particularly in resource-limited settings. A single low-
relapse before such approach can be regularly adopted. dose infusion alone is probably undesirable due to suboptimal
efficacy and is at risk of developing anti-rituximab antibodies
Retreatment as scheduled therapy with recurrent drug exposures [52]. It is noteworthy that in
adult protocols and some prospective pediatric trials [5, 8,
A third approach is a scheduled therapy, where rituximab is 19], each 375 mg/m2 dose is limited to a maximum of 500
repeated periodically at a regular interval, irrespective of B mg. While this limit should be applied to higher dosing
cell and clinical status. The rationale of this strategy is to ranges, it may be advisable to adequately dose young people
induce persistent B cell depletion and consequently disease receiving a low-dose regimen (600–700 mg in absolute dose
remission. Kimata et al. repeated rituximab (375 mg/m2 each) according to their body surface area) to avoid under-dosing
four times at 3-monthly intervals in five children with SDNS, and consequently a shorter B cell depletion.
and induced long-term remission without serious adverse We recommend prescribing rituximab cautiously in the
events [50]. Takahashi et al. reported that repeating rituximab youngest children, given the concerns of drug safety among
at 6-month intervals for 2 years effectively reduced relapse them. We also do not recommend redosing rituximab based
rates and achieved long-term remission in half of the recruited on B cell reconstitution or as a regular schedule, except in a
patients with complicated FRSDNS [51]. Nonetheless, signif- very limited group of children who have a clinical history of
icant side effects were observed in a high proportion of chil- very severe relapses needing hospitalization with massive ede-
dren [51], suggesting such frequent rituximab administrations ma and/or acute kidney injury. Many children, after receiving
might be excessive for adequate disease control. The effect of a few courses of rituximab, can be successfully managed with
persistent B cell depletion in a developing immunological other immunosuppressive agents, and never or only at a much
system is unknown and deserves attention. later time require further rituximab treatment. If regular ther-
apy is used, then it should be withheld every 2 to 3 treatment
Practical approach and the way forward cycles since some patients do naturally run into long-term
disease remission.
Optimal therapy of FRSDNS should effectively induce long- There are still many remaining questions regarding the op-
term remission with minimal toxicity related to steroids, ritux- timal rituximab regimen in steroid-sensitive nephrotic syn-
imab, and other immunosuppression. Cost is also an important drome. It is important to be aware that the above recommen-
consideration as rituximab is not readily affordable in many dations are based on limited data, predominantly from chil-
countries (2000 Euros per 500 mg rituximab). dren with complicated FRSDNS. For less severe patients re-
Our preferred practice at this present time is to use rituxi- ceiving rituximab as a first-line agent, the effects of dose and
mab in children with complicated FRSDNS after all other maintenance immunosuppression are likely different and an
treatment options have been tried. This means that the child alternative approach may be necessary. Treatment regimens
should typically have tried most treatments including every should thus be individualized and should balance the disease
other day low-dose steroids, levamisole, cyclophosphamide, severity, treatment efficacy, drug safety, tolerance to co-med-
CNI, and MMF before being eligible for rituximab. Using ication, adherence, cost, and family as well as physician pref-
rituximab as first-line steroid-sparing agent, not surprisingly, erence. In the future, new and reliable biomarkers, such as
Pediatr Nephrol (2021) 36:1397–1405 1403

switched memory B cells, anti-rituximab antibodies, and T 2. Which of the following regimens has shortest relapse-free
lymphocyte activation markers, may help to predict relapse survival?
and guide prophylactic treatments [53].
A. Low dose (375 mg/m2) alone
Uncertainties and outstanding research questions B. Medium dose (750 mg/m2) alone
C. Low dose (375 mg/m2) with maintenance therapy
Large scale prospective investigations are required to answer D. High dose (750 mg/m2) with maintenance therapy
outstanding research questions and can be grouped into a few 3. Which of the following B cell subsets is more relevant to
directions: relapse after rituximab?

1. Prognostication of patients’ response to rituximab. A. Transitional B cells

2. To establish the effective dosing regimen when rituximab B. Mature B cells
is used in children with uncomplicated FRSDNS. C. IgM Memory B cells
3. To identify the choice and optimal duration of mainte- D. Switched Memory B cells
nance immunosuppression to adjunct the rituximab effect. 4. How many patients develop persistent
4. To evaluate the long-term efficacy and safety profile for hypogammaglobulinemia following rituximab?
repeated rituximab therapies, especially in young chil-
dren. This may provide important data to guide subse- A. Less than 5%
quent treatments, understand the development of drug re- B. 5% to 10%
sistance, and justify repeated rituximab use. C. 10% to 15%
5. To investigate the implication and formulate the appropri- D. More than 15%
ate management of persistent hypogammaglobulinemia.
6. To identify and validate reliable biomarkers to predict
relapse and guide timely re-treatment. Keypoints

– Patient factors, rituximab dose, and use of maintenance

immunosuppression all influence treatment outcomes
– Low-dose rituximab alone is associated with shortest
Conclusion relapse-free survival and higher relapse risk
– Concomitant immunosuppression, notably MMF, may be
Rituximab is an effective and important therapy in children useful to extend remission especially with low-dose
with FRSDNS. New insights suggest patient factors, rituximab rituximab
dose, and use of concomitant immunosuppression all impact – Role of B cell monitoring may be limited due to discrep-
on treatment outcomes. Whereas rituximab appears to be gen- ancy between B cell population and relapse after
erally safe, cautions and regular monitoring are of particular rituximab
importance in young children to look for adverse events in- – There are growing concerns of persistent
cluding neutropenia, persistent hypogammaglobulinemia, and hypogammaglobulinemia and impaired immunity partic-
impaired vaccine competence. Treatment protocols should ularly in young children
therefore be individualized. International, multi-ethnic, pro-
spective studies are much needed to answer outstanding re- Answer: 1. D; 2. A; 3. D; 4. D
search questions and identify the optimal strategy for rituximab
in this patient population. Compliance with ethical standards

Conflict of interest The authors declare that they have no conflicts of

interest.
Questions

1. What factors determine the treatment response to

rituximab? References

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