Co-Administration of Roxadustat and Zinc Stabilizes Both Serum Copper and Zinc Concentrations in Patients Undergoing Hemodialysis

Abstract

Patients undergoing hemodialysis often require zinc supplementation owing to hypozincemia, which may reduce serum copper concentrations. However, hypoxia-inducible factor–prolyl hydroxylase inhibitors (HIF-PHIs), which are used to treat renal anemia, have been reported to increase serum copper. Therefore, this study investigates the effectiveness of a combination of HIF-PHIs and zinc for the stabilization of serum copper and zinc concentrations during zinc supplementation for patients undergoing hemodialysis with renal anemia and hypozincemia. The serum zinc and copper concentrations were retrospectively compared over an 8-month period in 20 patients being administered roxadustat (an HIF-PHI) and 20 controls. The changes in concentrations were tracked in participants taking roxadustat who initiated or increased zinc supplementation. The serum zinc concentrations of the participants were significantly higher (p < 0.001) during zinc supplementation, regardless of roxadustat administration. Post-roxadustat, the serum copper concentrations were significantly higher than those pre-roxadustat or in non-roxadustat-treated participants, irrespective of zinc supplementation (p < 0.005). Even post-roxadustat, the serum copper concentrations were significantly lower, with no increase during zinc supplementation (p < 0.040). When zinc supplementation was initiated or increased in participants taking roxadustat, copper and zinc concentrations were normalized. Thus, combining zinc supplementation with roxadustat prevents both an excessive increase in serum copper and a decrease in serum zinc.

Zinc Supplementation Enhances the Hematopoietic Activity of Erythropoiesis-Stimulating Agents but Not Hypoxia-Inducible Factor–Prolyl Hydroxylase Inhibitors

“…Serum copper concentrations in patients participating in this study were significantly higher in the roxadustat group compared with the darbepoetin alfa group. The possible reasons for this include the following: As previously reported [ 13 , 31 ], the use of HIF-PHI increases serum copper concentrations. Moreover, in this study, when arranged chronologically by patients, serum copper concentrations significantly increased from 12.2 ± 1.4 μmol/L to 17.7 ± 1.9 μmol/L after switching from darbepoetin alfa to roxadustat ( p < 0.05).…”

“…The supplementation of carnitine is adjusted to achieve a predialysis-free carnitine concentration of 180 μmol/L or higher [ 52 , 53 ]. Zinc levels are adjusted to ensure a serum concentration between 12.2 and 18.4 µmol/L, with the simultaneous monitoring of serum copper concentration [ 13 ].…”

“…Excessive increases in serum zinc and copper concentrations are also implicated in dementia [ 66 ]. However, this concern about serum copper concentrations is stabilized by the reductive effect of appropriate zinc supplementation [ 13 ].…”

“…Since HIF-PHI administration increases serum copper concentrations, zinc supplementation during HIF-PHI administration can stabilize copper concentrations, emphasizing the need for adequate zinc supplementation during HIF-PHI use [ 13 ]. However, patients prescribed high doses of zinc can develop iatrogenic copper deficiency [ 14 ]; thus, the proper balance of zinc and copper concentrations is important.…”

“…However, there have been many reports of concerns about a decrease in serum copper concentration due to zinc supplementation [ 15 , 16 ]. In patients undergoing hemodialysis, if serum zinc concentration exceeds 18.4 µmol/L (120 μg/dL), the serum copper concentration will fall below the standard value [ 13 , 15 ]. Conversely, it has been reported that an increase in the Cu/Zn ratio may further exacerbate inflammation [ 17 ], and higher Cu/Zn ratios appeared to be associated with higher Type 2 diabetes risk [ 18 ].…”