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Letters to the Editor
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Roxadustat for Renal Anemia in ESRD from PKD Patients: Is It Safe Enough?

Fei Liu, Jingjing Wang, Qing Ye, Haidong Fu and Jianhua Mao
JASN April 2021, 32 (4) 1005; DOI: https://doi.org/10.1681/ASN.2020111664
Fei Liu
1Department of Nephrology, Children’s Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou, China
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Jingjing Wang
1Department of Nephrology, Children’s Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou, China
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Qing Ye
2Department of Clinical Laboratory, Children’s Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou, China
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Haidong Fu
1Department of Nephrology, Children’s Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou, China
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Jianhua Mao
3Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
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  • anemia chronic kidney disease
  • polycystic kidney disease

Akizawa et al.1 report roxadustat’s noninferiority to darbepoetin alfa in treating hemodialysis-dependent CKD anemia in their phase 3 study. However, in this trial, we could not find the exact data of the primary disease of CKD or the proportion that polycystic kidney disease (PKD)1⇓⇓–4 accounts for. PKD is the fourth leading cause of ESKD in adults worldwide; however, in a phase 2 trial of roxadustat in CKD-associated anemia in Japanese patients, the ratio of polycystic kidney disease was 6.3% (five in 80).2

Roxadustat and other hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors induce hypoxia-like conditions within the cell by stabilizing HIFs and regulating the downstream pathway. Meanwhile, the HIF pathway has been identified as an important novel mechanism of cyst progression through chloride secretion, apoptosis, cell proliferation, cell metabolism, and inflammation in PKD.3 Further, application of a prolyl-hydroxylase inhibitor resulted in severe aggravation of the mild phenotype.4

Although HIF prolyl hydroxylase inhibitors offer several important advantages, we caution that the long-term use of roxadustat might induce the growth and enlargement of renal cysts in patients with PKD, which can lead to adverse events such as bleeding and infection. Given the data of these trials and hypothesis, the total kidney volume of patients with PKD should be monitored carefully, and these patients deserve long-term follow-up.

Disclosures

All authors have nothing to disclose.

Funding

This work was supported by grants from the Key Research and Development Plan of Zhejiang Province (2019C03028).

Footnotes

  • Published online ahead of print. Publication date available at www.jasn.org.

  • See related, “Authors' Reply,” on pages 1005–1007, and original article, “Phase 3, Randomized, Double-Blind, Active-Comparator (Darbepoetin Alfa) Study of Oral Roxadustat in CKD Patients with Anemia on Hemodialysis in Japan,” in Vol. 31, Iss. 7, on pages 1628–1639.

  • Copyright © 2021 by the American Society of Nephrology

References

  1. ↵
    1. Akizawa T,
    2. Iwasaki M,
    3. Yamaguchi Y,
    4. Majikawa Y,
    5. Reusch M
    : Phase 3, randomized, double-blind, active-comparator (darbepoetin alfa) study of oral roxadustat in CKD patients with anemia on hemodialysis in Japan. J Am Soc Nephrol 31: 1628–1639, 2020pmid:32493693
    OpenUrlAbstract/FREE Full Text
  2. ↵
    1. Akizawa T,
    2. Iwasaki M,
    3. Otsuka T,
    4. Reusch M,
    5. Misumi T
    : Roxadustat treatment of chronic kidney disease-associated anemia in Japanese patients not on dialysis: A phase 2, randomized, double-blind, placebo-controlled trial. Adv Ther 36: 1438–1454, 2019pmid:30953333
    OpenUrlCrossRefPubMed
  3. ↵
    1. Buchholz B,
    2. Eckardt K-U
    : Role of oxygen and the HIF-pathway in polycystic kidney disease. Cell Signal 69: 109524, 2020pmid:31904413
    OpenUrlCrossRefPubMed
  4. ↵
    1. Kraus A,
    2. Peters DJM,
    3. Klanke B,
    4. Weidemann A,
    5. Willam C,
    6. Schley G, et al
    .: HIF-1α promotes cyst progression in a mouse model of autosomal dominant polycystic kidney disease. Kidney Int 94: 887–899, 2018pmid:30173898
    OpenUrlCrossRefPubMed
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Journal of the American Society of Nephrology: 32 (4)
Journal of the American Society of Nephrology
Vol. 32, Issue 4
April 2021
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Roxadustat for Renal Anemia in ESRD from PKD Patients: Is It Safe Enough?
Fei Liu, Jingjing Wang, Qing Ye, Haidong Fu, Jianhua Mao
JASN Apr 2021, 32 (4) 1005; DOI: 10.1681/ASN.2020111664

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Roxadustat for Renal Anemia in ESRD from PKD Patients: Is It Safe Enough?
Fei Liu, Jingjing Wang, Qing Ye, Haidong Fu, Jianhua Mao
JASN Apr 2021, 32 (4) 1005; DOI: 10.1681/ASN.2020111664
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