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Abstract: TH-PO697

Four Cases of Serum Copper Excess in Patients With Renal Anemia Receiving a Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitor: A Possible Safety Concern

Session Information

  • Anemia and Iron Metabolism
    November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Anemia and Iron Metabolism

  • 200 Anemia and Iron Metabolism


  • Nakamura, Hironori, Department of Nephrology, Shinonoi General Hospital, Nagano, Japan
  • Mariko, Anayama, Department of Nephrology, Shinonoi General Hospital, Nagano, Japan
  • Ueda, Michiko, Department of Nephrology, Shinonoi General Hospital, Nagano, Japan
  • Nagasawa, Masaki, Department of Nephrology, Shinonoi General Hospital, Nagano, Japan
  • Makino, Yasushi, Department of Nephrology, Shinonoi General Hospital, Nagano, Japan

Copper is an indispensable trace metal element and is mainly absorbed in the stomach and small intestine and excreted into the bile. Hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) have emerged as a novel approach for renal anemia management. Many intestinal genes, including divalent metal transporter 1 (DMT1), duodenal cytochrome B (DCYTB), and copper transporter ATPase7A (ATP7A), related to iron or copper metabolism are transactivated by HlF-α, during iron deficiency.

Case Description

We first report four cases of patients with renal anemia who showed excess in serum copper level during roxadustat or daprodustat treatment, which were decreased to the normal level after discontinuing HIF-PHIs and changing the drug to darbepoetin alfa, suggesting that HIF-PHI is associated with serum copper excess shown in Fig 1.


In a rat model, roxadustat significantly increased expression of DMT1 and DCYTB mRNA and stabilized HIF-1α and HIF-2α in vitro. HIF-α protein levels rapidly declined after washout of roxadustat from cell cultures. Just as HIF-PHI modulates iron metabolism, such as absorption, sequestration and mobilization, HIF-PHI may also influence serum copper levels by mechanisms through copper absorption and/or redistribution via DMT1, ATP7A and copper transporter 1 in tissues. Therefore, it is urgent to examine the correlation between HIF-PHI use and serum copper levels because copper excess might be involved in several acute or chronic adverse events.

Changes of serum copper and days before, during, and after the HIF-PHI treatment. Halftone dot meshing shows the term of HIF-PHI treatment and its dose.