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Long-term outcome of childhood-onset complicated nephrotic syndrome after a multicenter, double-blind, randomized, placebo-controlled trial of rituximab

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Abstract

Background

Although rituximab effectively prevents relapses of complicated frequently relapsing nephrotic syndrome (FRNS) and steroid-dependent nephrotic syndrome (SDNS), data of long-term outcomes and safety are limited.

Methods

Fifty-one patients (age, 3–38 years) with childhood-onset complicated FRNS or SDNS, who received rituximab in investigator-initiated multicenter prospective trials were enrolled. Rituximab was administered at 375 mg/m2 once weekly for 4 weeks, and immunosuppressive agents were discontinued according to the study protocol. We investigated relapses, re-administration of immunosuppressive agents, additional rituximab treatment, body height, renal function, and late adverse events during the observation period.

Results

Forty-eight patients (94%) developed relapses during the observation period (median, 59 months) and the 50% relapse-free survival was 261 days. Thirty patients (59%) developed SDNS, 44 (86%) required re-administration of immunosuppressive agents, and 22 (43%) received additional rituximab treatment. All patients who were receiving immunosuppressive agents at rituximab treatment required either immunosuppressive agents or additional rituximab treatment. On the contrary, 5 of the 13 patients without immunosuppressive agents at rituximab treatment required neither immunosuppressive agents nor additional rituximab treatment and 3 of them did not develop relapse during observation period. Growth failure due to steroid toxicity did not progress and none of the patients developed chronic renal insufficiency. None of the patients suffered from rituximab-related late adverse events.

Conclusions

As most patients suffer from relapses after B-cell recovery, long-term immunosuppressive agents or additional rituximab treatment is necessary. However, some patients who can discontinue immunosuppressive agents before rituximab treatment may achieve long-term remission after rituximab treatment without immunosuppressive agents.

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Acknowledgements

The authors thank all patients and their families, in addition to the physicians who participated in the RCRNS studies and the present follow-up study. The authors thank the EDANZ group Japan for proofreading and editing the manuscript.

Author information

Authors and Affiliations

  1. Division of Nephrology and Rheumatology, National Center for Child Health and Development, 2-10-1, Okura, Setagaya-ku, Tokyo, 157-8535, Japan

    Koichi Kamei & Kenji Ishikura

  2. Division for Clinical Trials, Department of Clinical Research, Center for Clinical Research and Development, National Center for Child Health and Development, 2-10-1, Okura, Setagaya-ku, Tokyo, 157-8535, Japan

    Mayumi Sako

  3. Department of Pediatrics, Kurashiki Central Hospital, 1-1-1, Miwa, Kurashiki, Okayama, 710-8602, Japan

    Kunihiko Aya

  4. Department of Nephrology, Hyogo Prefectural Kobe Children’s Hospital, 1-6-7, Minamimachi, Minatojima, Chuo-ku, Kobe, Hyogo, 650-0047, Japan

    Ryojiro Tanaka

  5. Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan

    Kandai Nozu, Hiroshi Kaito & Kazumoto Iijima

  6. Department of Child Health and Welfare (Pediatrics), Graduate School of Medicine, University of the Ryukyus, 207, Azauehara, Nishihara-cho, Nakagami-gun, Okinawa, 903-0215, Japan

    Koichi Nakanishi

  7. Department of Pediatrics, Juntendo University Nerima Hospital, 3-1-10, Takanodai, Nerima-ku, Tokyo, 177-8521, Japan

    Yoshiyuki Ohtomo

  8. Department of Pediatric Nephrology, Tokyo Women’s Medical University, School of Medicine, 8-1, Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan

    Kenichiro Miura

  9. Department of Pediatrics, Nihon University Itabashi Hospital, 30-1, Oyaguchikamimachi, Itabashi-ku, Tokyo, 173-8610, Japan

    Shori Takahashi

  10. Division of Pediatrics, Tohoku Medical and Pharmaceutical University Hospital, 1-12-1, Fukumuro, Miyagino-ku, Sendai, Miyagi, 983-8512, Japan

    Tetsuji Morimoto

  11. Department of Nephrology, Tokyo Metropolitan Children’s Medical Center, 2-8-29, Musashidai, Fuchu, Tokyo, 183-8561, Japan

    Wataru Kubota

  12. Department of Pediatrics, Graduate School of Medicine, Yokohama City University, 3-9, Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan

    Shuichi Ito

  13. Department of Development Strategy, Center for Clinical Research and Development, National Center for Child Health and Development, 2-10-1, Okura, Setagaya-ku, Tokyo, 157-8535, Japan

    Hidefumi Nakamura

Authors
  1. Koichi Kamei
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  2. Kenji Ishikura
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  3. Mayumi Sako
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  4. Kunihiko Aya
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  5. Ryojiro Tanaka
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  6. Kandai Nozu
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  7. Hiroshi Kaito
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  8. Koichi Nakanishi
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  9. Yoshiyuki Ohtomo
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  10. Kenichiro Miura
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  11. Shori Takahashi
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  12. Tetsuji Morimoto
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  13. Wataru Kubota
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  14. Shuichi Ito
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  15. Hidefumi Nakamura
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  16. Kazumoto Iijima
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Consortia

on behalf of the Rituximab for Childhood-Onset Refractory Nephrotic Syndrome (RCRNS) Study Group

Corresponding author

Correspondence to Koichi Kamei.

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Conflicts of interest

Koichi Kamei has received lecture fees from Chugai Pharmaceutical. Kenji Ishikura has received lecture fees from Asahi Kasei Pharma, Chugai Pharmaceutical, Zenyaku Kogyo, and Novartis Pharma, and a consulting fee from Ono Pharmaceutical. Mayumi Sako has received grants from Eisai, lecture fees and/or consulting fees from Astellas Pharma and Zenyaku Kogyo. Kunihiko Aya has received lecture fees from Asahi Kasei Pharma. Kandai Nozu has received lecture fees from Chugai Pharmaceutical and Asahi Kasei Pharma. Koichi Nakanishi has received lecture fees from Otsuka Pharmaceutical and Asahi Kasei Pharma. Shuichi Ito has received lecture fees and/or grants from Chugai Pharmaceutical, Zenyaku Kogyo, Asahi Kasei Pharma, Novartis Pharma, and Astellas Pharma. Hidefumi Nakamura is an advisor to Takeda Pharmaceutical and received lecture fees from Mitsubishi Tanabe Pharma. Kazumoto Iijima has received grants from Novartis Pharma, Pfizer Japan, Kyowa Hakko Kirin, AbbVie, Daiichi Sankyo, Teijin Pharma, CSL Behring, and Astellas Pharma, lecture fees and/or consulting fees from Pfizer Japan, Asahi Kasei Pharma, Novartis Pharma, Zenyaku Kogyo, Daiichi Sankyo, Chugai Pharmaceutical, Astellas Pharma, and Takeda Pharmaceutical.

Ethics approval

The design and execution of this study were in accordance with the ethical standards of the Declaration of Helsinki. The protocol was approved by the Ethics Committee of the National Center for Child Health and Development (No. 774).

Informed consent

For this type of study, formal informed consent is not required.

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Kamei, K., Ishikura, K., Sako, M. et al. Long-term outcome of childhood-onset complicated nephrotic syndrome after a multicenter, double-blind, randomized, placebo-controlled trial of rituximab. Pediatr Nephrol 32, 2071–2078 (2017). https://doi.org/10.1007/s00467-017-3718-0

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