Periodically repeated rituximab administrations in children with refractory nephrotic syndrome: 2-year multicenter observational study

Takahashi, Toshiyuki; Okamoto, Takayuki; Sato, Yasuyuki; Yamazaki, Takeshi; Hayashi, Asako; Aoyagi, Hayato; Ueno, Michihiko; Kobayashi, Norio; Uetake, Kimiaki; Nakanishi, Masayoshi; Ariga, Tadashi

doi:10.1007/s00467-018-4063-7

Cited by 24 publications

(29 citation statements)

References 34 publications

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“…Complete or partial remission was observed in 40% of the present study's patients, respectively. Some of the SSNS and SRNS patients in the present study received periodic RTX dose, as reported earlier (24). Based on the present findings, we think that such dosing regimens might have a positive effect on remission.…”

Section: Discussionsupporting

confidence: 54%

Rituximab for Children With Difficult-to-Treat Nephrotic Syndrome: Its Effects on Disease Progression and Growth

et al. 2019

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Background: Since the early 2000s rituximab (RTX) has been thought of as an alternative treatment for steroid-sensitive nephrotic syndrome (SSNS) and steroid-resistant nephrotic syndrome (SRNS). Objective: This study aimed to determine the effects of RTX treatment on disease outcome and growth in pediatric SSNS and SRNS patients. Materials and Methods: The medical records of pediatric SSNS and SRNS patients that began RTX treatment at the mean age of 10.8 ± 5.1 years between 2009 and 2017 were retrospectively reviewed. Additionally, the effect of RTX on growth was evaluated based on patient height, weight, and BMI z scores. Results: The study included 41 children, of which 21 had SSNS and 20 had SRNS. Mean age at diagnosis of NS was 5.8 ± 4.7 years. Mean duration of post-RTX treatment follow-up was 2.3 ± 1.6 years. Among the SSNS patients, 6 and 11 patients were steroid free and calcineurin inhibitor free at the last follow-up visit, respectively. The 1-year cumulative steroid and calcineurin inhibitor doses both decreased after RTX treatment, as compared to before RTX ( P = 0.001 and P = 0.015, respectively). The median height z -score at the time of RTX initiation was −1.2 and the median height z -score at the last follow-up visit was −0.6 ( P = 0.044). The median BMI z -score decreased from 1.6 (IQR; 0.9–3.0) at the time RTX was initiated to 1.1 IQR; [(−0.7)−2.5] at the last follow-up visit ( P = 0.007). At the last follow-up visit 4 SRNS patients had complete remission and 4 had partial remission. The 1-year cumulative steroid dosage in the SRNS patients decreased significantly after RTX, as compared to before RTX ( P = 0.001). The median height z -score at the time of RTX initiation was −0.8 and the median height z -score at the last follow-up visit was −0.7 ( P = 0.81). The median BMI z -score decreased from 0.3 at the time RTX was initiated to −0.1 at the last follow-up visit ( P = 0.11). Conclusion: RTX has a more positive effect on disease outcome and growth in SSNS patients than in those with SRNS.

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Section: Discussionsupporting

confidence: 54%

Rituximab for Children With Difficult-to-Treat Nephrotic Syndrome: Its Effects on Disease Progression and Growth

et al. 2019

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“…A prospective study, aimed at monitoring changes in IgG levels in pediatric steroid-dependent INS treated with repeated rituximab infusions to maintain B-cell depletion for 18 months, reported an increased risk of prolonged hypogammaglobulinemia in patients with pre-existing low IgG levels (10). Reduced IgG levels were also observed after 2 years of a standardized protocol of four single rituximab infusions at 6-months interval in children with difficult-to-treat INS (11). In contrast, a retrospective short-term analysis of anti-CD20-related adverse events in a large cohort of multidrug-dependent INS children treated with rituximab or ofatumumab (a fully human anti-CD20 monoclonal antibody) showed normal total IgG levels and stability of anti-tetanus and anti-hepatitis B virus (HBV) IgG titers, albeit at 12-months (12).…”

Section: Introductionmentioning

confidence: 95%

Prolonged Impairment of Immunological Memory After Anti-CD20 Treatment in Pediatric Idiopathic Nephrotic Syndrome

et al. 2019

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Anti-CD20 therapy is effective in idiopathic nephrotic syndrome (INS). However, transient or sustained hypogammaglobulinemia predisposing to an increased risk of infectious diseases can follow treatment in some patients. We analyzed the long-term effects of anti-CD20 therapy on immunological memory in 27 frequently-relapsing/steroid-dependent INS pediatric patients after more than 4 years from the first and at least 2 years from the last anti-CD20 infusion. Twenty-one INS children, never treated with anti-CD20 and under an intense oral immunosuppression with prednisone, mycophenolate mofetil, and calcineurin inhibitors were also included as control group. Levels of circulating B-cell subpopulations, total serum immunoglobulins and IgG and memory B cells directed against hepatitis B virus (HBV) and tetanus were determined and correlated with clinical characteristics. Nine patients never relapsed after more than 2 years from the last anti-CD20 administration (5 after the first, 3 after the second, and 1 after the fifth infusion). At last follow-up, most patients showed a complete recovery and normalization of total (27/27), transitional (27/27), and mature-naïve B cells (25/27). However, a sustained and significant reduction of total memory (20/27) and switched memory (21/27) B cells was found in most patients. 11/27 patients showed hypogammaglobulinemia at last follow-up and, among these, four presented with a severe hypogammaglobulinemia (IgG < 160 mg/dl). In contrast, no patient in the control group developed a severe hypogammaglobulinemia. Age at the time of first anti-CD20 administration was positively associated with IgG levels at last follow-up ( p = 0.008); accordingly, younger patients had an increased risk of hypogammaglobulinemia ( p = 0.006). Furthermore, severe hypogammaglobulinemia and delayed switched memory B-cell reconstitution were more frequent in non-relapsing patients. Reduced IgG levels against HBV and tetanus were observed at baseline and further declined at last follow-up. Antigen-specific memory B-cells were induced by re-immunization, but specific IgG titers remained low. In conclusion, anti-CD20 therapy can be disease-modifying in some INS patients. However, a prolonged impairment of immunological memory occurs frequently, independently from the number of anti-CD20 infusions, particularly in younger patients. Re-immunization may be necessary in these patients.

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“…Takahashi reported on the efficacy of a single rituximab infusion given routinely, regardless of proteinuria, every 6 months for 2 years in children with SRNS. Although this helped in controlling the NS, it was associated with significant side effects, making further studies important before this approach could be widely recommended (93).…”

Section: Factors That May Affect the Clinical Response Of Rituximab Imentioning

confidence: 99%

“…B cell recovery has been used in some protocols to indicate the need for another dose of rituximab to maintain B cell depletion and NS remission (36, 93, 111). Although this approach has been reported to be beneficial in these studies, larger studies are still needed to validate this practice, since it is also known that some individuals can experience NS relapses despite having B cell depletion (36, 49, 112), and repeat dosing of rituximab based on B cell reconstitution rather than NS relapse may expose children to unnecessary rituximab treatment and increase the risk of drug-induced complications.…”

Section: Biomarkers Of Response To Rituximabmentioning

confidence: 99%

Rituximab Use in the Management of Childhood Nephrotic Syndrome

2019

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Childhood nephrotic syndrome is a challenging and often persistent renal disorder, and its incidence varies between different ethnicities and regions. Corticosteroids have been the main treatment for decades and are effective in most children with idiopathic NS, although 10–15% of these children become steroid resistant. Furthermore, some initially steroid sensitive children follow a steroid dependent or frequently relapsing course and are therefore at increased risk for developing steroid toxicity. In such children, alternative immunosuppressive medications are used to induce and/or maintain remission of NS. One such drug, rituximab, is a monoclonal antibody directed against the B lymphocyte CD20 marker which induces depletion of B cells, and has shown promising results in the management of NS in children. In this review, we summarize recent studies on the efficacy and safety of rituximab in the different types of childhood nephrotic syndrome, the known and potential mechanisms of action of rituximab, its possible complications and side effects, and the available and potential biomarkers of rituximab activity.

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Periodically repeated rituximab administrations in children with refractory nephrotic syndrome: 2-year multicenter observational study

Abstract: Our protocol was useful and safe for refractory NS. However, RTX administration four times might have been excessive in patients who had no relapse by 1 year after the initial RTX administration. Further investigation of the most appropriate method of RTX administration is required.

Cited by 24 publications

References 34 publications

Rituximab for Children With Difficult-to-Treat Nephrotic Syndrome: Its Effects on Disease Progression and Growth

Rituximab for Children With Difficult-to-Treat Nephrotic Syndrome: Its Effects on Disease Progression and Growth

Prolonged Impairment of Immunological Memory After Anti-CD20 Treatment in Pediatric Idiopathic Nephrotic Syndrome

Rituximab Use in the Management of Childhood Nephrotic Syndrome

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