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Renal prognoses by different target hemoglobin levels achieved by epoetin beta pegol dosing to chronic kidney disease patients with hyporesponsive anemia to erythropoiesis-stimulating agent: a multicenter open-label randomized controlled study

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Abstract

Background

There is no evidence regarding appropriate target hemoglobin levels in chronic kidney disease (CKD) patients with an erythropoiesis-stimulating agent (ESA)-hyporesponsiveness. Therefore, we conducted a randomized controlled study in non-dialysis dependent CKD (NDD-CKD) patients with ESA-hyporesponsiveness, comparing results of intensive versus conservative treatment to maintain hemoglobin levels.

Methods

This was a multicenter, open-label, randomized, parallel-group study conducted at 89 institutions. Among NDD-CKD patients, those with ESA-hyporesponsive renal anemia were randomly assigned to an intensive treatment group, to which epoetin beta pegol was administered with target hemoglobin level of 11 g/dL or higher, or conservative treatment group, in which the hemoglobin levels at enrollment (within ± 1 g/dL) were maintained. The primary endpoint was the time to the first kidney composite event defined as (1) transition to renal replacement therapy (dialysis or renal transplantation); (2) reduction of estimated glomerular filtration rate (eGFR) to less than 6.0 mL/min/1.73 m2; or (3) reduction of eGFR by 30% or more. Secondary endpoints were kidney function (change rate in eGFR), cardiovascular (CV) events, and safety.

Results

Between August 2012 and December 2015, 385 patients were registered, and 362 patients who met the eligibility criteria were enrolled. There was no significant difference in kidney survival or in CV events between the two groups. However, the incidences of the 3 types of kidney composite events tended to differ.

Conclusions

In NDD-CKD patients with ESA-hyporesponsive renal anemia, the aggressive administration of ESA did not clearly extend kidney survival or result in a significant difference in the incidence of CV events.

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Acknowledgements

The authors would like to thank Drs. Hiroshi Ito, Takanari Kitazono and Takashi Wada for evaluation of kidney and CV events; Drs. Masashi Suzuki, Yoshiharu Tsubakihara and Satoshi Morita for independent data monitoring; and the many investigators, nurses and clinical research coordinators who contributed to this study.

Funding

The funding for this study was provided by Chugai Pharmaceutical Co., Ltd., on the basis of a commissioning contract, and was provided to EP-CRSU Co., Ltd. (Japanese Contract Research Organization) that handled administration tasks, etc., for the study secretariat and data center. The funding party, Chugai Pharmaceutical Co., was involved with the conception of the study, and provision of information, but not with planning or conducting the study, or analyzing or interpreting the results.

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Authors and Affiliations

  1. Department of Nephrology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan

    Kazuhiko Tsuruya

  2. Department of Kidney Disease and Hypertension, Osaka General Medical Center, Osaka, Japan

    Terumasa Hayashi

  3. Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan

    Hiroyasu Yamamoto

  4. Aoba Hospital, Tokyo, Japan

    Hiroki Hase

  5. Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, Kobe, Japan

    Shinichi Nishi

  6. Division of Clinical Medicine, Department of Nephrology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan

    Kunihiro Yamagata

  7. Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan

    Masaomi Nangaku

  8. Department of Nephrology and Laboratory Medicine, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan

    Takashi Wada

  9. Biostatistics Section, Department of Data Science, Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, Japan

    Yukari Uemura

  10. Department of Integrated Science and Engineering for Sustainable Society, Chuo University, Tokyo, Japan

    Yasuo Ohashi

  11. Fukuoka Renal Clinic, Fukuoka, Japan

    Hideki Hirakata

Authors
  1. Kazuhiko Tsuruya
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  2. Terumasa Hayashi
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  3. Hiroyasu Yamamoto
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  4. Hiroki Hase
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  5. Shinichi Nishi
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  6. Kunihiro Yamagata
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  7. Masaomi Nangaku
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  8. Takashi Wada
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  9. Yukari Uemura
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  10. Yasuo Ohashi
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  11. Hideki Hirakata
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Consortia

RADIANCE-CKD Study Investigators

Contributions

HH leaded this study as principal investigator. HH, HY, KT, HH, SN, MN, TW, T, YU and YO participated in the interpretation of study results, and were involved in this study design, and approval of the manuscript. HH, HY, KT, HH, SN, MN, TW and TH were investigators of this study. YO and YU conducted the statistical analysis.

Corresponding author

Correspondence to Kazuhiko Tsuruya.

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Conflict of interest

K. Tsuruya has received speakers fee as honoraria and grants from Chugai and Kyowa Kirin. T. Hayashi has received speakers fee as honoraria from Chugai and Kyowa Kirin. H. Yamamoto has received speakers fee as honoraria from Chugai and Kyowa Kirin. H. Hase has received grants from Chugai and Kyowa Kirin. S. Nishi has received speakers fee as honoraria and grants from Chugai and Kyowa Kirin. K. Yamagata has received speakers fee as honoraria and grants from Chugai and Kyowa Kirin. M. Nangaku has received speakers fee as honoraria from Chugai, Kyowa Kirin and Kissei, grants from Chugai and Kyowa Kirin, research funding from Kyowa Kirin and manuscript fee from Kyowa Kirin. T. Wada has received grants from Chugai and Kyowa Kirin, and research funding from Kyowa Kirin. Y. Uemura has received speakers fee as honoraria from Chugai. Y. Ohashi has received speakers fee as honoraria from Chugai. H. Hirakata has speakers fee as honoraria from Chugai.

Human rights

This study was conducted in compliance with the Declaration of Helsinki and “Ethical Guidelines for Clinical Studies” by the Ministry of Health, Labour and Welfare and in accordance with International Council for Harmonization Good Clinical Practice (ICH-GCP) guidelines. The study was approved by an independent central ethics committee and was registered in the University Hospital Medical Information Network (UMIN) database (UMIN000008617). Study treatments performed were covered by ordinary health insurance. This report was prepared according to the Consolidated Standards of Reporting Trials (CONSORT).

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Written informed consent was obtained from all included participants included in the study.

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Tsuruya, K., Hayashi, T., Yamamoto, H. et al. Renal prognoses by different target hemoglobin levels achieved by epoetin beta pegol dosing to chronic kidney disease patients with hyporesponsive anemia to erythropoiesis-stimulating agent: a multicenter open-label randomized controlled study. Clin Exp Nephrol 25, 456–466 (2021). https://doi.org/10.1007/s10157-020-02005-4

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