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. Author manuscript; available in PMC: 2026 Jun 5.
Published in final edited form as: Pediatr Nephrol. 2025 Jun 5;40(10):3121–3127. doi: 10.1007/s00467-025-06811-4

Utilization of anti‑CD20 antibodies for treatment of childhood nephrotic syndrome, 2010 to 2022

Michelle R Denburg 1,2,3, Kathryn Hirabayashi 4, Amy Goodwin Davies 4, Hanieh Razzaghi 4, Vikas R Dharnidharka 5, Bradley P Dixon 6, Joseph T Flynn 7, Caroline A Gluck 8, Mark M Mitsnefes 9, William E Smoyer 10, Susan L Furth 1,2,3, Christopher B Forrest 2,4,11
PMCID: PMC12378964  NIHMSID: NIHMS2097050  PMID: 40473981

Abstract

Background

A growing body of evidence supports the efficacy of the type I anti-CD20 monoclonal antibody, rituximab, in the management of children with frequently relapsing or steroid-dependent nephrotic syndrome. We examined temporal trends and described current patterns in the use of anti-CD20 antibodies and other corticosteroid-sparing drug therapies in a large multi-institutional population of children with nephrotic syndrome.

Methods

Data came from PEDSnet, a clinical research network that aggregates electronic health record data at several children’s healthcare organizations in the United States. Patients with at least one inpatient, emergency, or outpatient physician encounter between January 2010 and November 2022 who met our published computable phenotype algorithm for nephrotic conditions were included. Children with systemic lupus erythematosus or congenital/genetic nephrotic diagnoses were excluded. Treatments were measured from nephrotic syndrome diagnosis to kidney transplant or most recent encounter.

Results

Among 6,892,137 patients across 6 centers, 2962 met criteria for nephrotic conditions (0.4 per 1000 patients). 852 (28.8%) had at least one native kidney biopsy. Nearly half of the population was exposed to at least one steroid-sparing agent, most of whom had exposure to multiple agents. 524 (17.7%) patients were exposed to rituximab, and utilization of rituximab increased over the 12-year study period. Similar trends were observed for mycophenolate and tacrolimus. Concurrently, use of cyclosporine and cyclophosphamide decreased.

Conclusion

Use of rituximab to manage nephrotic syndrome has steadily increased, and tacrolimus, mycophenolate, and rituximab are currently the most commonly used steroid-sparing agents for childhood nephrotic syndrome.

Keywords: Pediatric, Nephrotic syndrome, Steroid-sparing agents, Rituximab, Tacrolimus, Mycophenolate mofetil

Introduction

Idiopathic nephrotic syndrome is the most common acquired kidney disease in childhood but is rare on a population level, with an annual incidence of about 1–17/100,000 children. The majority of children with nephrotic syndrome, particularly those with minimal change disease, respond to corticosteroid therapy. However, up to 90% of children with nephrotic syndrome will relapse, half of whom will develop frequently relapsing or steroid-dependent disease, both of which pose higher burdens of disease- and treatment-related complications [1]. Cumulative steroid exposure both from the high doses and long durations of therapy required to treat nephrotic syndrome is associated with considerable toxicity, including hypertension, diabetes, obesity, Cushingoid appearance, short stature, osteopenia, fractures, infections, and psychological disorders [2, 3]. Therefore, steroid-sparing immunosuppression is critically important in the management of most children with nephrotic syndrome.

Considerable practice pattern variation exists in the choice of agent for steroid-sparing therapy. Recently published clinical practice recommendations from the International Pediatric Nephrology Association (IPNA) recommend initial introduction of cyclophosphamide, calcineurin inhibitors or mycophenolate mofetil, and using rituximab as a third-line agent if one of these fails to maintain remission [4]. A growing body of evidence supports the efficacy of rituximab, a type I anti-CD20 monoclonal antibody, in the management of children with frequently relapsing or steroid-dependent nephrotic syndrome. Multiple clinical trials have demonstrated it to be effective in decreasing relapse frequency, maintaining remission, and facilitating the weaning and withdrawal of corticosteroid and other immunosuppressive therapy. Randomized controlled trials have also found rituximab to be superior to tacrolimus and low-dose mycophenolate in steroid-dependent nephrotic syndrome [5–9]. Data on ofatumumab, a fully humanized type I monoclonal antibody with stronger affinity for CD20, and obinutuzumab, a fully humanized type II monoclonal antibody, has been limited to small case series. A single center randomized controlled trial in children with steroid- and calcineurin inhibitor-dependent nephrotic syndrome showed that a single dose of ofatumumab was not superior to a single dose of rituximab in maintaining remission at 12 and 24 months [10].

To gain further insight into use of these newer monoclonal agents in children with nephrotic syndrome, we examined temporal trends and described current patterns in the use of anti-CD20 antibodies and other corticosteroid-sparing drug therapies in a large multi-institutional United States (US) population of children with nephrotic syndrome. This study was conducted within PEDSnet, a multi-institutional national clinical research network, and leveraged a computable phenotype algorithm which was previously demonstrated to reliably identify children with glomerular disease [11].

Methods

Data came from PEDSnet (pedsnet.org), a clinical research network that aggregates electronic health record (EHR) data from several children’s healthcare organizations across the US. PEDSnet institutions included in this analysis were Children’s Hospital of Philadelphia; Children’s Hospital Colorado; Cincinnati Children’s Hospital Medical Center; Nationwide Children’s Hospital; Nemours Children’s Health System (a Delaware and Florida health system); and Seattle Children’s Hospital. PEDSnet standardizes EHR data across institutional data marts to the PEDSnet common data model, which is based on the Observational Medical Outcomes Partnership (OMOP) common data model [12, 13]. PEDSnet has accrued data for over 14 million children seen since 2009 from all inpatient and outpatient clinical settings. The PEDSnet database includes data from patients who reside in all 50 states. This study was covered under Children’s Hospital of Philadelphia Institutional Review Board (IRB) protocol #14–011242.

From the PEDSnet population (database version 5.2), we selected patients with at least one inpatient, emergency, or outpatient physician encounter between January 2010 and November 2022 who met our published EHR-based computable phenotype algorithm for nephrotic conditions [11] and were aged 1 to < 22 on the date of their initial nephrotic syndrome diagnosis. This algorithm was previously evaluated across 8 health systems in PEDSnet and demonstrated excellent classification accuracy for the identification of glomerular disease and the subpopulation of children with nephrotic conditions, inclusive of idiopathic nephrotic syndrome (nephrotic syndrome without a biopsy) or biopsy-based minimal change nephropathy, focal segmental glomerulosclerosis, or membranous nephropathy. We excluded children with systemic lupus [14] or with one or more congenital or genetic nephrotic diagnoses (see https://github.com/PEDSnet/nephrotic_syndrome for logic and codes used to define the cohort). Given that steroid resistance is the primary indication for biopsy in childhood nephrotic syndrome, we stratified the study population by whether they had undergone native kidney biopsy as a surrogate indicator of steroid resistance. The majority of children with nephrotic syndrome who do not undergo biopsy and are treated with steroid-sparing agents can be presumed to be frequently relapsing or steroid-dependent.

Follow-up time for the cohort began on the day that the first diagnosis for nephrotic syndrome was recorded and ended at the earliest of either the most recent face-to-face clinical encounter or, if applicable, kidney transplant. Exposure to rituximab, ofatumumab, and obinutuzumab was evaluated among this cohort. Exposure to other commonly used corticosteroid-sparing immunosuppressive therapies, including mycophenolate, oral and intravenous cyclophosphamide, and the calcineurin inhibitors (CNI), cyclosporine, and tacrolimus, was assessed for comparison. The proportion of patients exposed to a therapy within a given calendar year was computed via the count of patients with nephrotic syndrome exposed to the therapy within that year, divided by the count of nephrotic syndrome patients with a visit following their first nephrotic syndrome code which occurred during or after that year.

Results

From among 6,892,137 patients with at least one physician encounter across 6 centers, 7762 patients met criteria for glomerular disease, 2962 of whom met criteria for nephrotic conditions and did not have SLE or a genetic nephrotic diagnosis (0.4 per 1000 patients). Of these 2962 patients, 852 (28.8%) had at least one native kidney biopsy. The median age at first nephrotic diagnosis code was 7.0 years (interquartile range [IQR] 4.0, 12.3) among those without a biopsy and 10.9 years (IQR 5.7, 15.3) among those who were biopsied. Fifty-seven percent of those without a biopsy were male, and 54% of those biopsied were male.

Forty-nine percent of the cohort received at least one of the following steroid-sparing agents: rituximab, mycophenolate, tacrolimus, cyclosporine, or cyclophosphamide. Overall, 524 (17.7%) patients were exposed to rituximab; < 11 (< 0.4%) were exposed to ofatumumab, which was only present in the data since 2019, and < 11 (< 0.4%) received obinutuzumab, which was only present in the data since 2018. Median age at initiation of rituximab was 9.8 years (IQR 6.5, 13.2) among the no biopsy group and 11.8 years (IQR 8.2, 15.8) among the biopsy group. Two hundred sixty (50%) of patients received two doses at initiation (within 45 days and inclusive of the first dose), 110 (21%) received one dose, and 79 (15%) received 4 doses. The maximum time between first and last dose of rituximab was 12.4 years among the no biopsy group and 11.2 years among the biopsy group. There were 819 (28%) patients exposed to tacrolimus, 174 (6%) to cyclosporine, 758 (26%) to mycophenolate, and 165 (6%) to cyclophosphamide.

As highlighted in Fig. 1, utilization of rituximab increased over the 12-year study period and even more so since 2016. Similar trends were observed for mycophenolate and tacrolimus. Concurrently, utilization of cyclosporine and the alkylating agent cyclophosphamide decreased. As expected, tacrolimus was most frequently utilized among those who had a kidney biopsy. Utilization of intravenous/intramuscular immunoglobulin G (IVIG) remained low (< 3%) across calendar time (Supplemental Fig. 1). Figure 2 displays linear regressions estimating proportions of patients with drug exposure for each drug of interest, with year as a predictor. Increasing utilization is indicated via the positive slopes observed for rituximab, mycophenolate and tacrolimus, while decreasing utilization is observed for cyclosporine and cyclophosphamide, indicated by negative slopes.

Fig. 1.

Fig. 1

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Temporal trends in utilization of steroid-sparing agents. a Full cohort; b patients who underwent native kidney biopsy; c patients without kidney biopsy

Fig. 2.

Fig. 2

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Linear regressions of trends in utilization of steroid-sparing agents. a Linear regressions modeling proportions of patients with a drug exposure, with year as a predictor; regression lines are labelled with their slopes (rituximab’s slope of β = 0.005 indicates that with each additional year, the proportion of patients with evidence of rituximab utilization increases by 0.005. Cyclophosphamide’s slope of β = − 0.002 indicates that with each additional year, the proportion of patients with evidence of cyclophosphamide utilization decreases by 0.002)

Figure 3 a shows the frequency of single versus multiple drug exposures. The majority of patients exposed to a steroid-sparing agent received at least one other agent, and this was particularly the case for rituximab; only 94 of the 524 patients who received rituximab had not been treated with another steroid-sparing agent. Figure 3 b shows a heat map of patients exposed to two or more drug classes (with cyclosporine and tacrolimus considered together as CNI). The greatest overlap in exposure was for CNI and mycophenolate (N = 411, 14%). There were 353 (12%) patients with exposure to both rituximab and CNI, and 264 patients (9%) with exposure to both rituximab and mycophenolate. One hundred ninety-eight (7%) patients had exposure to rituximab, CNI, and mycophenolate.

Fig. 3.

Fig. 3

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Single versus multiple exposures to steroid-sparing agents. a Single exposures to drugs: patients were exposed to the drug shown and were not exposed to the other 4 drugs. Multiple exposures to drugs: patients were exposed to the drug shown, in addition to at least one of the other four drugs. b Counts of patients exposed to two or more agents. Calcineurin inhibitors (CNI) include patients with exposures to tacrolimus or cyclosporine. The counts in gray indicate patients who have been exposed to a drug. Patients may have been exposed to other drugs in addition to drug 1 and drug 2

Discussion

This analysis highlights that utilization of rituximab for the management of nephrotic syndrome has been steadily increasing and that use of fully humanized anti-CD20 therapies remains rare. Utilization of cyclophosphamide and cyclosporine have declined considerably. Tacrolimus, mycophenolate, and rituximab are currently the most commonly used steroid-sparing agents for childhood nephrotic syndrome. As anticipated, nearly half of the population with nephrotic syndrome was exposed to at least one steroid-sparing agent, most of whom had exposure to multiple agents.

It should be noted that of the steroid-sparing agents used in the management of childhood nephrotic syndrome, only cyclophosphamide is FDA approved for this indication. While their efficacy has been established through a number of randomized controlled trials, the real-world comparative effectiveness of steroid-sparing agents for maintaining remission and their comparative safety profiles have not been systematically evaluated. As a national network of pediatric health systems, PEDSnet provides real-world clinical data that can be leveraged for comparative effectiveness research in rare diseases such as nephrotic syndrome. Given the expanding use of anti-CD20 antibody therapies in this patient population, these longitudinal EHR data provide an important opportunity to complement randomized controlled trials in determining both long-term effectiveness and safety. The IPNA clinical practice recommendations graded the quality of evidence comparing adverse outcomes of steroid-sparing agents in children with nephrotic syndrome to be very low or low [4], and long-term safety data is especially limited. Prior randomized controlled trials of steroid-sparing immunosuppression did not extend follow-up beyond 24 months, and the majority had follow-up periods of 12 months or less [4, 5]. The IPNA guideline specifically calls for research to “assess the long-term safety of nephrotic syndrome immunosuppression therapy” [4]. PEDSnet includes data on patients seen at participating institutions since 2009 and therefore offers a unique opportunity to evaluate long-term safety of steroid-sparing immunosuppression. As utilization of fully humanized anti-CD20 therapies increases and new drugs are developed, real-world data resources such as PEDSnet can serve as invaluable resources for enhanced post marketing surveillance of adverse drug reactions as well as effectiveness in comparison to existing therapies.

The IPNA clinical practice recommendations also specifically call for research to “determine the safety of therapy with rituximab, specifically the risk of transient or sustained hypogammaglobulinemia” [4]. While recognizing that utilization of IVIG does not necessarily indicate specific treatment for, nor the prevalence of, hypogammaglobulinemia, its utilization remained low over the study period. While the majority of patients who received steroid-sparing immunosuppression were exposed to multiple agents, this was particularly the case for those who received rituximab. This reflects its initial utilization as second-line steroid-sparing therapy. Initial trials of rituximab focused on establishing non-inferiority to steroids [15, 16] as well as its efficacy in reducing relapse risk among children with frequently relapsing and steroid-dependent nephrotic syndrome who were dependent on CNI or mycophenolate therapy [17–20]. Subsequent randomized controlled trials have found rituximab to be superior to tacrolimus and low-dose mycophenolate as first-line therapy in steroid-dependent nephrotic syndrome [5–9]. The largest comparative study to date (N = 120) demonstrated higher relapse-free survival over 12 months with rituximab compared to tacrolimus (90% vs. 63%, p < 0.001) and lower risk of infection with rituximab (22% vs. 43%) [8]. Recent findings indicating that anti-nephrin and other autoantibodies may play a role in the pathogenesis of podocytopathies may have implications for expanded and targeted use of B cell depleting anti-CD20 agents in subsets of patients with steroid-sensitive nephrotic syndrome [21–24].

There are limitations to these findings. Most notably, these data are from tertiary pediatric centers in the US and therefore may not reflect usage patterns in resource-limited settings, where patients may not have access to newer agents due to cost or local availability. We also recognize this population is heterogeneous in terms of underlying glomerular diagnoses and steroid responsiveness. This analysis involved secondary use of real-world EHR data through which categories of steroid response cannot currently be ascertained through diagnosis codes. Given that there is also no existing computable phenotype algorithm for classification of steroid response in nephrotic syndrome using EHR or claims data, we used kidney biopsy as a surrogate marker for steroid resistance. We did not have histopathology results because the free text data of biopsy reports is not included in the PEDSnet common data model. However, based on our prior study showing that membranous nephropathy made up 3.4% of biopsy-based glomerular disease in PEDSnet [11], the proportion of the cohort with this histopathologic diagnosis was likely very low.

In summary, this study demonstrates that tacrolimus, mycophenolate, and rituximab are the mainstay of steroid-sparing immunosuppression for children with nephrotic syndrome across the US. We would like to highlight the opportunity to study the long-term safety and effective-ness of these agents in large populations of children with nephrotic syndrome, already receiving these medications, through collaborative multi-institutional pragmatic trials.

Supplementary Material

Supplemental Figure 1 - Utilization of intravenous/intramuscular immunoglobulin G (IVIG) remained low (< 3%) across calendar time

Supplementary Information The online version contains supplementary material available at 10.1007/s00467-025-06811-4.

Funding

This work was supported by PCORI grant award CRN-2020–007 and NIDDK grant P50DK114786.

Footnotes

Declarations

Conflict of interest Dr. Dixon has consultancy agreements with Apellis Pharmaceuticals, Novartis Pharmaceuticals, Alexion Astra Zeneca Rare Disease, Arrowhead Pharmaceuticals, and Calliditas Therapeutics, and has received research funding from Apellis Pharmaceuticals, Novartis Pharmaceuticals, Alexion Astra Zeneca Rare Disease, Ultragenyx Pharmaceuticals, and Roche Genentech. The remaining authors have no relevant disclosures.

Disclaimer The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIDDK, the National Institutes of Health, the Department of Health and Human Services, or the government of the United States.

Data availability

The results reported in this manuscript are based on detailed individual-level patient data compiled by members of PEDSnet. Due to the high risk of reidentification based on unique patterns in the clinical data, even when demographic identifiers have been removed, patient privacy regulations prohibit us from releasing the individual-level data publicly. However, logic and codes used to define the cohort are publicly available and can be accessed here: [https://github.com/PEDSnet/nephrotic_syndrome].

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplemental Figure 1 - Utilization of intravenous/intramuscular immunoglobulin G (IVIG) remained low (< 3%) across calendar time
NIHMS2097050-supplement-Supplemental_Figure_1_-_Utilization_of_intravenous_intramuscular_immunoglobulin_G__IVIG__remained_low____3___across_calendar_time.tiff (107.3MB, tiff)

Data Availability Statement

The results reported in this manuscript are based on detailed individual-level patient data compiled by members of PEDSnet. Due to the high risk of reidentification based on unique patterns in the clinical data, even when demographic identifiers have been removed, patient privacy regulations prohibit us from releasing the individual-level data publicly. However, logic and codes used to define the cohort are publicly available and can be accessed here: [https://github.com/PEDSnet/nephrotic_syndrome].

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