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Role of Erythropoiesis-Stimulating Agents in Cardiovascular Protection in CKD Patients: Reappraisal of Their Impact and Mechanisms

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Abstract

Erythropoiesis-stimulating agents (ESAs) have markedly reduced the need for blood transfusion for renal anemia and are included in standard therapies for patients with chronic kidney disease (CKD). Various protective effects of ESAs on the cardiovascular system have been discovered through basic research, and the effects have received much attention because the rates of cardiovascular events and mortality are high in CKD patients. However, randomized clinical trials did not provide strong evidence that ESAs exert cardioprotection in humans, including CKD patients. It is difficult to assess the cardioprotective effects of ESAs in CKD patients through the clinical data that has been reported to date because the relationship between hemoglobin level rather than ESA dose and cardiovascular event rates was examined in most studies. Interestingly, recent studies using a rat model of CKD showed that the infarct size-limiting effect of an ESA was lost when its dose was increased to a level that normalized blood hemoglobin levels, suggesting that the optimal dose of an ESA for myocardial protection is less than the dose required to normalize hemoglobin levels. Furthermore, animal models of traditional coronary risk factors or comorbidities were resistant to the cardioprotective effects of ESAs because of interruptions in signal-mediated mechanisms downstream of erythropoietin receptors. In this review, we briefly discuss basic and clinical data on the impact of anemia on coronary and systemic circulation, the effects of CKD on the cardiovascular system, and the multiple pharmacological actions of ESAs to examine whether the ESAs that are prescribed for renal anemia exert any cardioprotection in patients with CKD.

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Reproduced from Nishizawa et al. [102]

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Reproduced from Nishizawa et al. [102]

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Acknowledgements

We thank Drs. Michinori Hirata and Ryohei Kawasaki, Product Research Department, Chugai Pharmaceutical Co., Ltd., Kanagawa, Japan, for valuable suggestions and support for the present work. We are grateful to Mr. Stewart Chisholm and editors at Springer Nature Author Services for proofreading and editing of the manuscript.

Funding

This study was supported by Grant-in Aid for Scientific Research from the Japan Society for the Promotion of Science (17K16016, 19K08522, 19K08544, 21K08035), a Grant for Education and Research from Hokkaido University of Science, and a Grant for Research from Chugai Pharmaceutical Co., Ltd.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Hokkaido University of Science, 15-4-1, Maeda-7, Teine-ku, Sapporo, Japan

    Tetsuji Miura

  2. Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan

    Tetsuji Miura, Tatsuya Sato, Toshiyuki Yano, Takayuki Miki & Keitaro Nishizawa

  3. Department of Cellular Physiology and Signal Transduction, Sapporo Medical University School of Medicine, Sapporo, Japan

    Tatsuya Sato & Noritsugu Tohse

  4. Department of Pharmacology, Faculty of Pharmaceutical Sciences, Hokkaido University of Science, Sapporo, Japan

    Akira Takaguri

  5. Department of Cardiology and Diabetes, Oji General Hospital, Tomakomai, Japan

    Takayuki Miki

  6. Department of Nephrology, Asahikawa Red Cross, Hospital, Asahikawa, Japan

    Keitaro Nishizawa

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TeM had the idea for the article, TeM and AT performed the literature search, and TS, TY, TaM, NT, and KN performed data analysis. The first draft of the manuscript was written by TeM and AT and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Tetsuji Miura.

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Animal experiments included in this article were conducted in strict accordance with the Guide for the Care and Use of Laboratory Animals published by National Research Council of the National Academies, USA (2011) and were approved by the Animal Use Committee of Sapporo Medical University (16–097).

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All authors consented to publish this study.

Conflict of Interest

This study was partly supported by a grant from Chugai Pharmaceutical, Tokyo, Japan as stated above.

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Miura, T., Sato, T., Yano, T. et al. Role of Erythropoiesis-Stimulating Agents in Cardiovascular Protection in CKD Patients: Reappraisal of Their Impact and Mechanisms. Cardiovasc Drugs Ther 37, 1175–1192 (2023). https://doi.org/10.1007/s10557-022-07321-3

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