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Role of Zinc and Copper in Erythropoiesis in Patients on Hemodialysis

Open AccessPublished:March 02, 2022DOI:https://doi.org/10.1053/j.jrn.2022.02.007
      Plasma zinc concentrations are decreased in patients on hemodialysis; zinc supplementation increases hemoglobin levels and reduces erythropoietin-stimulating agent treatments. However, inappropriate zinc supplementation causes copper deficiency. This review discusses the roles of zinc and copper throughout erythropoiesis; it also describes erythropoiesis-stimulating nutritional therapy that avoids copper deficiency, while providing safe zinc supplementation. In early erythropoiesis, erythropoietin regulates erythrocyte precursor proliferation and survival via zinc finger transcription factors. Mature blood cell formation and functional activation are regulated by zinc-mediated hormones, vitamins, and growth peptides. Zinc antagonizes the uptake of divalent cations (e.g., iron and copper) in erythrocyte precursors. Copper is required for iron transfer from cells to blood, ensuring dietary iron absorption and systemic iron distribution. In patients with copper deficiency, copper supplementation is initially performed, followed by zinc supplementation to manage hypozincemia. Serum zinc and copper measurements are needed at 2- to 3-month intervals during zinc supplementation to prevent copper deficiency.

      Keywords

      Introduction and Purpose

      The number of patients requiring hemodialysis treatment because of end-stage renal disease is increasing,
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      The current and future landscape of dialysis.
      and plasma zinc concentrations are decreased in patients on hemodialysis.
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      Effects of erythropoietin on trace elements in patients with chronic renal failure undergoing hemodialysis.
      Experimental studies have shown that zinc supplementation stimulates erythropoiesis (i.e., red blood cell [RBC] formation) in rats.
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      Zinc supplementation stimulates red blood cell formation in rats.
      Consistent with this finding, zinc supplementation during hemodialysis has been shown to increase hemoglobin levels in patients with end-stage renal disease
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      Zinc deficiency anemia and effects of zinc therapy in maintenance hemodialysis patients.
      ,
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      • et al.
      Oral zinc supplementation reduces the erythropoietin responsiveness index in patients on hemodialysis.
      ; zinc supplementation reportedly reduces the amount of erythropoietin-stimulating agents used in such patients.
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      • Abe M.
      • Okada K.
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      Oral zinc supplementation reduces the erythropoietin responsiveness index in patients on hemodialysis.
      The mechanism underlying the association between zinc and hemoglobin production involves the incorporation of zinc into GATA-1 (a zinc finger protein transcription factor that regulates various genes involved in RBC synthesis
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      • DeVilbiss A.W.
      • Pope N.J.
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      Transcriptional mechanisms underlying hemoglobin synthesis.
      ) (Fig. 1A). Therefore, when zinc is deficient, the GATA-1 transcription factor activity in hematopoiesis decreases, leading to reduced hemoglobin production.
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      Three-dimensional solution structure of a single zinc finger DNA-binding domain.
      ,
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      • et al.
      Heme regulates gene expression by triggering Crm1-dependent nuclear export of Bach1.
      Furthermore, zinc interacts with signaling cascades such as the growth hormone (GH) to insulin-like growth factor-1 (IGF-1) pathway to influence RBC synthesis
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      • Tolis G.
      Assessment of endocrine and nutritional status in age-related catabolic states of muscle and bone.
      (Fig. 1B). Accordingly, zinc is regarded as an important erythroid differentiation factor. However, the precise roles of zinc and copper (a closely related trace mineral) throughout erythropoiesis, as well as the prevention of copper deficiency during zinc supplementation for hypozincemia, have not yet been fully investigated.
      Figure thumbnail gr1
      Figure 1Schema summarizing the effects of minerals on (A) GATA-1 signaling and RBC synthesis, (B) GH and IGF-1 during RBC synthesis, and (C) DNA synthesis and hemoglobin synthesis (in combination with vitamins). Cu, copper; DNA, deoxyribonucleic acid; Fe, iron; GH, growth hormone; IGF-1, insulin-like growth factor-1; RBC, red blood cell; Zn, zinc.
      Although a considerable portion of the literature regarding erythropoiesis has focused on iron and erythropoietin, this review article discusses the roles of zinc, copper, and other nutrients (e.g., vitamins, folic acid, and selenium) during erythropoiesis (Fig. 1C). This article also describes safe zinc supplementation that does not cause copper deficiency in patients on hemodialysis.

      Zinc and Copper Concentrations in Patients on Hemodialysis

      Meta-analysis of trace elements in whole blood, serum, or plasma
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      Trace elements in hemodialysis patients: a systematic review and meta-analysis.
      has shown that zinc levels in patients on chronic maintenance hemodialysis appear to be lower than those in the general population, while copper levels tend to be higher (see Table 1 for detailed comparison of healthy, hemodialysis, and end-stage renal disease populations). However, there are some limitations of using whole blood, serum, or plasma to assess overall zinc status; for example, serum zinc levels exhibit circadian dynamics
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      and strong associations with serum protein levels.
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      Furthermore, zinc levels are related to inflammatory status.
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      The types of zinc deficiency in patients on hemodialysis include insufficient intake, impaired absorption, and excess loss. The causes of insufficient zinc intake are related to aging, polypharmacy, and inadequate dietary protein and energy (undernutrition).
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      The causes of impaired absorption include ingestion of absorption inhibitors (e.g., oxalic acid, phytic acid, polyphosphoric acid, dietary fiber, calcium, magnesium, and iron) and combined use of zinc chelating agents.
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      Table 1Serum Concentrations of Copper and Zinc in Healthy Controls, Chronic Kidney Disease Patients, and Hemodialysis Patients
      Copper (μg/dL)Zinc (μg/dL)References
      HealthyFree serum Cu10-15Brewer 2012
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      Wilson's disease.
      Ceruloplasmin18-35 (mg/dL)
      Ceruloplasmin Cu
      Each 1 mg/dL of ceruloplasmin contributes 3 μg/dL of serum Cu.
      54-105
      Total serum Cu
      Total serum Cu = Free serum Cu + ceruloplasmin Cu.
      64-120
      105.26 ± 19.6379.44 ± 10.28Attar 2019
      • Attar T.
      Levels of serum copper and zinc in healthy adults from the west of Algeria.
      102 ± 592 ± 3Zima et al. 1998
      • Zima T.
      • Mestek O.
      • Nĕmecek K.
      • et al.
      Trace elements in hemodialysis and continuous ambulatory peritoneal dialysis patients.
      78.5 ± 13.0Toro-Román et al. 2021
      • Toro-Román V.
      • Siquier-Coll J.
      • Bartolomé I.
      • Grijota F.J.
      • Muñoz D.
      • Maynar-Mariño M.
      Copper concentration in erythrocytes, platelets, plasma, serum and urine: influence of physical training.
      108.0 ± 8.593.3 ± 12.1Batista et al. 2006
      • Batista M.N.
      • Cuppari L.
      • de Fátima Campos Pedrosa L.
      • et al.
      Effect of end-stage renal disease and diabetes on zinc and copper status.
      Male84.9 ± 0.8Hennigar et al. 2018
      • Hennigar S.R.
      • Lieberman H.R.
      • Fulgoni 3rd, V.L.
      • McClung J.P.
      Serum zinc concentrations in the US population are related to sex, age, and time of blood draw but not dietary or supplemental zinc.
      Female80.6 ± 0.6
      CKDDM130.02 ± 36.784.1 ± 17.7Batista et al. 2006
      • Batista M.N.
      • Cuppari L.
      • de Fátima Campos Pedrosa L.
      • et al.
      Effect of end-stage renal disease and diabetes on zinc and copper status.
      NDM109.7 ± 26.281.2 ± 19.8
      eGFR 30-59109 ± 2076 ± 16Shih et al. 2012
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      • Chen C.A.
      • Lin H.Y.
      • Huang Y.L.
      • Lin C.C.
      Changes in levels of copper, iron, zinc, and selenium in patients at different stages of chronic kidney disease.
      eGFR 15-29124 ± 1769 ± 13
      Hemodialysis102 ± 669 ± 3Zima et al. 1998
      • Zima T.
      • Mestek O.
      • Nĕmecek K.
      • et al.
      Trace elements in hemodialysis and continuous ambulatory peritoneal dialysis patients.
      57.4 ± 2.4Rashidi et al. 2009
      • Rashidi A.A.
      • Salehi M.
      • Piroozmand A.
      • Sagheb M.M.
      Effects of zinc supplementation on serum zinc and C-reactive protein concentrations in hemodialysis patients.
      CKD, chronic kidney disease; Cu, copper; DM, patients with type 2 diabetes; eGFR, estimated glomerular filtration rate (mL/min/1.73 m2); NDM, nondiabetic patients.
      Data are expressed as mean ± standard deviation.
      Each 1 mg/dL of ceruloplasmin contributes 3 μg/dL of serum Cu.
      Total serum Cu = Free serum Cu + ceruloplasmin Cu.
      A cause of excess loss of zinc is removal by hemodialysis. A total of 80% of zinc in the blood is found in RBCs, most of which is carbonic anhydrase (zinc-requiring enzyme).
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      Carbon dioxide narcosis in the terminal stage of hemodialysis therapy: a case report with the possible pathophysiologies and the treatment methods.
      The remaining zinc (approximately 20%) is present in serum, 60%-80% of which is bound to albumin and is not removed by hemodialysis.
      • Graig F.A.
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      Distribution in blood and excretion of Zn65 in man.
      Other zinc in serum is bound to alpha-2 macroglobulin,
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      Biological consequences of zinc deficiency in the pathomechanisms of selected diseases.
      but a small amount of this is bound to amino acids, such as cysteine, which are removed by hemodialysis.
      Zinc levels are positively correlated with levels of albumin, hematocrit, and prealbumin.
      • Hosokawa S.
      • Yoshida O.
      Effect of recombinant human erythropoietin (rHuEPO) on protein, zinc (Zn), nickel (Ni) and manganese (Mn) in patients undergoing chronic haemodialysis.
      Zinc levels are thought to be an indicator of nutritional status because zinc levels are high when people are well nourished.
      • Grzegorzewska A.E.
      • Mariak I.
      Zinc as a marker of nutrition in continuous ambulatory peritoneal dialysis patients.
      There are varying reports of copper concentrations in patients on hemodialysis, such as moderate copper deficiency, high copper levels, or copper toxicity.
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      • DiSilvestro R.A.
      • Nahman Jr., N.S.
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      Copper-related blood indexes in kidney dialysis patients.
      Cases of copper deficiency caused by zinc supplementation for hypozincemia have been reported.
      • Koi S.
      • Arai K.
      • Nogami A.
      • et al.
      Impaired hematopoiesis due to copper deficiency in a hemodialysis patient supplemented with zinc. [Article in Japanese].
      ,
      • Yaldizli O.
      • Johansson U.
      • Gizewski E.R.
      • Maschke M.
      Copper deficiency myelopathy induced by repetitive parenteral zinc supplementation during chronic hemodialysis.
      Therefore, the balance between zinc and copper is clinically important during zinc supplementation.

      Roles of Zinc, Copper, and Other Factors in the Process of Red Blood Cell Hematopoiesis

      Iron and erythropoietin are widely regarded as important components in hematopoiesis. To more fully understand the need for careful management of zinc and copper levels in patients on hemodialysis, it is important to consider the roles of zinc, copper, and other factors in hematopoiesis.

      Erythropoiesis

      In the early stage of erythropoiesis, erythropoietin and IGF-1 act together to initiate hematopoiesis
      • Takahashi A.
      Carnitine in dialysis patients. [Article in Japanese].
      (Fig. 2, top right). IGF-1 is a hormone that is mainly produced in the liver by the action of GH. GH and IGF-1 are also related to zinc (Fig. 2, top right)
      • Lytras A.
      • Tolis G.
      Assessment of endocrine and nutritional status in age-related catabolic states of muscle and bone.
      ; the liver stores a small amount of systemic zinc,
      • Mangray S.
      • Zweit J.
      • Puri P.
      Zinc deficiency in cirrhosis: micronutrient for thought?.
      along with considerable amounts of copper and iron.
      • Roberts E.A.
      • Sarkar B.
      Liver as a key organ in the supply, storage, and excretion of copper.
      ,
      • Anderson E.R.
      • Shah Y.M.
      Iron homeostasis in the liver.
      Zinc supplementation for pregnant women with anemia results in an increase in IGF-1 levels,
      • Nishiyama S.
      • Kiwaki K.
      • Miyazaki Y.
      • Hasuda T.
      Zinc and IGF-I concentrations in pregnant women with anemia before and after supplementation with iron and/or zinc.
      which are correlated with an increase in hemoglobin levels and the RBC count. This suggests that IGF-1 plays a role in increasing RBCs.
      Figure thumbnail gr2
      Figure 2Schema showing zinc, copper, and other factors involved in erythropoiesis.
      • Jurowski K.
      • Szewczyk B.
      • Nowak G.
      • Piekoszewski W.
      Biological consequences of zinc deficiency in the pathomechanisms of selected diseases.
      In the early stage of erythropoiesis (top right, dark gray boxes/arrows), Epo and IGF-1 act together to initiate hematopoiesis. IGF-1 is produced by the action of GH, but GH and IGF-1 are also related to zinc. When multipotent stem cells change to proerythroblasts (top left), Epo binds to the Epo receptor, and GATA-1, which is an erythroid differentiation factor, is released (middle, dark gray boxes/arrows). Proerythroblasts change to basophilic erythroblasts, polychromatophilic erythroblasts, and orthochromatophilic erythroblasts (left). There is a zinc finger in the structure of GATA-1. When Epo is stopped or the dose is reduced, caspase 3 is released and it mediates degradation of GATA-1 to cause neocytolysis, but carnitine inhibits caspase 3 and prevents apoptosis (middle, dark gray boxes/arrows). Vitamin D acts as an adjuvant in the early stages of erythroid differentiation (top left). Vitamin D receptor also has a zinc finger as a structural factor. When GATA-1 is released and erythroid differentiation begins, DNA synthesis begins, which requires vitamin B12 and folic acid (middle right, lighter gray arrows/boxes). Hemoglobin synthesis also begins; vitamin B6 is required at the beginning of this synthesis (bottom right, lightest gray arrows/boxes). Zinc antagonizes divalent cations, such as iron and copper, during the absorption process at DMT1. Copper is required for ferroportin. After reticulocytes are formed, copper/zinc superoxide dismutase acts as a scavenger, and carnitine and vitamin E prolong the lifespan of erythrocytes (bottom, white boxes/arrows). ALT, alanine aminotransferase; AST, aspartate aminotransferase; Cu, copper; DNA, deoxyribonucleic acid; Epo, erythropoietin; Fe, iron; GH, growth hormone; IGF-1, insulin-like growth factor-1; MCV, mean corpuscular volume; SOD, superoxide dismutase; Zn, zinc.
      Several minerals, namely magnesium, selenium, and zinc, are important determinants of IGF-1 bioactivity.
      • Maggio M.
      • De Vita F.
      • Lauretani F.
      • et al.
      IGF-1, the cross road of the nutritional, inflammatory and hormonal pathways to frailty.
      Plasma GH levels are increased during intravenous zinc administration, and IGF-1 and IGF-binding protein 3 levels are increased after oral zinc supplementation.
      • Alves C.X.
      • Vale S.H.L.
      • Dantas M.M.G.
      • et al.
      Positive effects of zinc supplementation on growth, GH, IGF1, and IGFBP3 in eutrophic children.
      Therefore, GH and IGF-1 levels decrease when zinc is deficient and increase with zinc supplementation (Fig. 1B). Zinc supplementation in older men significantly increases hematocrit levels, RBCs, and testosterone levels.
      • Haboubi N.Y.
      • Baker M.A.
      • Gyde O.H.
      • Small N.A.
      • Haboubi N.
      Zinc supplementation and erythropoiesis in the elderly.
      Therefore, an increase in RBCs because of zinc supplementation may occur via androgen metabolism. Erythropoietin then regulates erythrocyte production by delaying deoxyribonucleic acid (DNA) degradation and preventing apoptosis (programmed cell death)
      • Obeng E.
      Apoptosis (programmed cell death) and its signals - a review.
      of erythroid progenitor cells.
      • Koury M.J.
      • Bondurant M.C.
      Erythropoietin retards DNA breakdown and prevents programmed death in erythroid progenitor cells.

      Erythropoietin and Release of GATA-1

      When multipotent stem cells change to proerythroblasts (Fig. 2, top left), erythropoietin binds to the erythropoietin receptor, leading to the release of GATA-1 (Fig. 2, middle; Fig. 3A). GATA-1 and friend of GATA-1 (FOG-1; a GATA-1 cofactor) form a complex and interact to regulate transcriptional activity for erythroid differentiation.
      • Chlon T.M.
      • Crispino J.D.
      Combinatorial regulation of tissue specification by GATA and FOG factors.
      Proerythroblasts then change to basophilic erythroblasts, polychromatophilic erythroblasts, and orthochromatophilic erythroblasts (Fig. 2, left).
      • Zhao W.
      • Kitidis C.
      • Fleming M.D.
      • Lodish H.F.
      • Ghaffari S.
      Erythropoietin stimulates phosphorylation and activation of GATA-1 via the PI3-kinase/AKT signaling pathway.
      GATA-1 and FOG-1 require zinc for bridging by the zinc finger protein in the structure
      • Bresnick E.H.
      • Martowicz M.L.
      • Pal S.
      • Johnson K.D.
      Developmental control via GATA factor interplay at chromatin domains.
      ,
      • Fox A.H.
      • Liew C.
      • Holmes M.
      • Kowalski K.
      • Mackay J.
      • Crossley M.
      Transcriptional cofactors of the FOG family interact with GATA proteins by means of multiple zinc fingers.
      (Fig. 3B). Therefore, in the event of zinc deficiency, GATA-1 cannot be produced. Additionally, when erythropoietin stimulation is interrupted or the erythropoietin dose is reduced, caspase 3 (a key component of apoptosis
      • Asadi M.
      • Taghizadeh S.
      • Kaviani E.
      • et al.
      Caspase-3: structure, function, and biotechnological aspects.
      ) is released, disrupting GATA-1 and causing neocytolysis (selective destruction of erythrocytes formed during hypoxia to increase the oxygen transport capacity of blood
      • Mairbäurl H.
      Neocytolysis: how to get rid of the extra erythrocytes formed by stress erythropoiesis upon descent from high altitude.
      ) (Fig. 2, middle). However, the synergistic actions of zinc and carnitine (a branched nonessential amino acid with diverse functions
      • Flanagan J.L.
      • Simmons P.A.
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      • Willcox M.D.
      • Garrett Q.
      Role of carnitine in disease.
      ) suppress the cleavage of caspase 3 (Fig. 2, middle)
      • Qi S.N.
      • Zhang Z.F.
      • Wang Z.Y.
      • Yoshida A.
      • Ueda T.
      L-carnitine inhibits apoptotic DNA fragmentation induced by a new spin-labeled derivative of podophyllotoxin via caspase-3 in Raji cells.
      ; this suppression prevents apoptosis in RBCs,
      • Perry D.K.
      • Smyth M.J.
      • Stennicke H.R.
      • et al.
      Zinc is a potent inhibitor of the apoptotic protease, caspase-3. A novel target for zinc in the inhibition of apoptosis.
      thus inhibiting neocytolysis.
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      Pharmacological use of L-carnitine in uremic anemia: has its full potential been exploited?.
      In contrast, combined depletion of zinc and copper promotes apoptosis.
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      • Koh J.Y.
      • Yoon Y.H.
      Depletion of intracellular zinc and copper with TPEN results in apoptosis of cultured human retinal pigment epithelial cells.
      Figure thumbnail gr3
      Figure 3GATA-1: signaling and structure. (A) Schema showing the relationship between erythropoietin and GATA-1 during early erythropoiesis. (B) Zinc finger bridging in the GATA-1 structure.
      • Roberts E.A.
      • Sarkar B.
      Liver as a key organ in the supply, storage, and excretion of copper.

      Vitamin D Acts as an Adjuvant

      Vitamin D acts as an adjuvant in the early stages of erythroid cell differentiation (Fig. 2, top left).
      • Deicher R.
      • Hörl W.H.
      Hormonal adjuvants for the treatment of renal anaemia.
      Zinc is also involved in this interaction because the vitamin D receptor contains the zinc finger, which requires zinc as a structural factor.
      • Wan L.Y.
      • Zhang Y.Q.
      • Chen M.D.
      • Liu C.B.
      • Wu J.F.
      Relationship of structure and function of DNA-binding domain in vitamin D receptor.
      Vitamin D receptor expression is reduced with zinc deficiency.
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      • Gao Y.
      • Xu J.
      • Shen X.M.
      Effect of zinc deficiency on the protein expression of vitamin D receptor and calcium binding protein in growth-stage rats duodenal mucosa.
      Zinc supplementation increases vitamin D receptor levels and increases the effect of vitamin D, resulting in a significant decrease in parathyroid hormone.
      • Takahashi A.
      Decrease in 1-81PTH after administration of Polaprezinc in hemodialysis patients. [Article in Japanese].

      Initiation of DNA Synthesis

      When erythroid differentiation is begun by GATA-1, DNA synthesis begins, which requires folic acid (as a source of tetrahydrofolate, a cofactor for nucleic acid synthesis
      • Froese D.S.
      • Fowler B.
      • Baumgartner M.R.
      Vitamin B12 , folate, and the methionine remethylation cycle-biochemistry, pathways, and regulation.
      ) and vitamin B12 (to ensure sufficient levels of active tetrahydrofolate
      • Froese D.S.
      • Fowler B.
      • Baumgartner M.R.
      Vitamin B12 , folate, and the methionine remethylation cycle-biochemistry, pathways, and regulation.
      ), as well as selenium (to regulate expression levels of DNA repair enzymes
      • Yildiz A.
      • Kaya Y.
      • Tanriverdi O.
      Effect of the interaction between selenium and zinc on DNA repair in association with cancer prevention.
      ) (Fig. 1C; Fig. 2, middle right).
      • Koury M.J.
      • Ponka P.
      New insights into erythropoiesis: the roles of folate, vitamin B12, and iron.
      If vitamin B12 and folic acid are insufficient, mean corpuscular volume (i.e., mean RBC volume) becomes high because cells are unable to divide effectively.
      • Kaferle J.
      • Strzoda C.E.
      Evaluation of macrocytosis.
      Selenium deficiency also induces macrocytosis (i.e., greatly increased RBC volume, indicative of various systemic illnesses).
      • Vinton N.E.
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      • Strobel C.T.
      • Ament M.E.
      Macrocytosis and pseudoalbinism: manifestations of selenium deficiency.
      When supplementing vitamin B12, it is poorly absorbed by oral intake.
      • Carmel R.
      How I treat cobalamin (vitamin B12) deficiency.
      In patients on hemodialysis, administering vitamin B12 by intravenous injection from the hemodialysis circuit is possible. Although B vitamins are classified as water-soluble, vitamin B12 accumulates in the liver after intravenous injection.
      • Joske R.A.
      The vitamin B12 content of human liver tissue obtained by aspiration biopsy.
      Therefore, the maximum effect of vitamin B12 supplementation in patients with end-stage renal disease is achieved by injection rather than oral intake.
      • Amini M.
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      • Atlasi R.
      Vitamin B12 supplementation in end stage renal diseases: a systematic review.
      Folic acid supplementation is effective by starting with 5 mg/day and gradually reducing it to 15 mg/week or less.
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      • Hultberg B.
      Treatment with different doses of folic acid in haemodialysis patients: effects on folate distribution and aminothiol concentrations.

      Initiation of Hemoglobin Synthesis

      After DNA synthesis begins, hemoglobin synthesis also begins, but vitamin B6 is required in this early stage (Fig. 2, bottom right). Before hemoglobin is made from globin and heme, iron binds to the center of protoporphyrin, which is the skeleton of heme, and heme is formed. Protoporphyrin is made from succinyl-coenzyme A and glycine in the mitochondria. Vitamin B6 is required as a coenzyme of aminolevulinic acid synthase during its synthesis.
      • Ferreira G.C.
      Heme synthesis.
      Because water-soluble vitamins are removed by hemodialysis, alanine aminotransferase levels may be low in patients on hemodialysis owing to vitamin B6 deficiency.
      • Chimata M.
      • Masaoka H.
      • Fujimaki M.
      • et al.
      Low serum aminotransferase activity in patients undergoing regular hemodialysis.
      Iron is required in the subsequent hematopoietic stage, but zinc antagonizes divalent cations, such as iron and copper, in the absorption process at divalent metal transporter 1 (DMT1; a transporter of ferrous iron and some divalent metal ions across plasma and endosomal membranes
      • Mims M.P.
      • Prchal J.T.
      Divalent metal transporter 1.
      ) (Fig. 4, left).
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      Iron, copper, and zinc transport: inhibition of divalent metal transporter 1 (DMT1) and human copper transporter 1 (hCTR1) by shRNA.
      The total amount of ionic species affects absorption of zinc, and a total dose of iron exceeding 25 mg may produce a measurable effect on zinc absorption.
      • Whittaker P.
      Iron and zinc interactions in humans.
      Figure thumbnail gr4
      Figure 4Absorption mechanism of iron, zinc, and copper in the digestive tract.
      • Deicher R.
      • Hörl W.H.
      Hormonal adjuvants for the treatment of renal anaemia.
      ,
      • Yildiz A.
      • Kaya Y.
      • Tanriverdi O.
      Effect of the interaction between selenium and zinc on DNA repair in association with cancer prevention.
      In addition to iron (Fe2+), DMT1 transports divalent cations, such as zinc (Zn2+) and copper (Cu2+); it provides a common pathway for gastrointestinal absorption of these metal ions (left). When iron is pumped from ferroportin, copper is required for hephaestin. Metallothionein has the ability to bind to heavy metals via the thiol group of cysteine residues; it typically binds to zinc, other heavy metals can compete for binding with metallothionein. Metallothionein is removed by hemodialysis; as zinc levels increase, iron and copper levels decrease. DMT1, divalent metal transporter 1; Dcytb, duodenal cytochrome B; CTR1, copper transporter 1; ATP7A, ATPase copper transporting alpha.
      Because patients on hemodialysis often take iron-containing phosphorus adsorbents continuously for a long period, regular serum zinc concentration tests may be necessary. Additionally, when iron is pumped from ferroportin (an exporter protein that transfers iron from cells to blood,
      • Ward D.M.
      • Kaplan J.
      Ferroportin-mediated iron transport: expression and regulation.
      ensuring iron distribution between tissues and iron absorption from dietary intake), copper is required for hephaestin (a transmembrane copper-dependent ferroxidase that transports iron from intestinal enterocytes into blood,
      • Petrak J.
      • Vyoral D.
      Hephaestin--a ferroxidase of cellular iron export.
      ensuring iron absorption from dietary intake) (Fig. 4, left).
      • Chen H.
      • Attieh Z.K.
      • Su T.
      • et al.
      Hephaestin is a ferroxidase that maintains partial activity in sex-linked anemia mice.
      Therefore, care must be taken because copper deficiency anemia may occur if excessive zinc supplementation is administered.
      • Duncan A.
      • Yacoubian C.
      • Watson N.
      • Morrison I.
      The risk of copper deficiency in patients prescribed zinc supplements.

      Erythrocyte Maturation After Reticulocyte Formation

      After reticulocyte formation, copper/zinc superoxide dismutase (an enzymatic antioxidant that neutralizes superoxide
      • Lewandowski Ł.
      • Kepinska M.
      • Milnerowicz H.
      The copper-zinc superoxide dismutase activity in selected diseases.
      ) acts as a scavenger, and carnitine and vitamin E prolong the lifespan of erythrocytes (Fig. 2, bottom).
      • Bonomini M.
      • Zammit V.
      • Pusey C.D.
      • De Vecchi A.
      • Arduini A.
      Pharmacological use of L-carnitine in uremic anemia: has its full potential been exploited?.
      Copper/zinc superoxide dismutase reduces oxidative stress caused by iron metabolism,
      • Koskenkorva-Frank T.S.
      • Weiss G.
      • Koppenol W.H.
      • Burckhardt S.
      The complex interplay of iron metabolism, reactive oxygen species, and reactive nitrogen species: insights into the potential of various iron therapies to induce oxidative and nitrosative stress.
      but its effect is thought to be reduced in hypozincemia and copper deficiency. Therefore, zinc and copper play important roles in the hematopoietic process of erythrocytes.

      Safe Zinc Supplementation Without Copper Deficiency

      With regard to the balance of zinc, copper, and iron, zinc and iron have a competitive antagonistic effect during absorption. Oral iron supplementation inhibits zinc absorption, but not copper.
      • Troost F.J.
      • Brummer R.J.
      • Dainty J.R.
      • Hoogewerff J.A.
      • Bull V.J.
      • Saris W.H.M.
      Iron supplements inhibit zinc but not copper absorption in vivo in ileostomy subjects.
      Notably, zinc antagonizes divalent cations, such as iron and copper, in the process of absorption by DMT1 (Fig. 4, left). In addition to iron, DMT1 in the gastrointestinal mucosa transports divalent cations, such as zinc and copper, and is a common pathway for absorption in the gastrointestinal tract.
      • Espinoza A.
      • Le Blanc S.
      • Olivares M.
      • Pizarro F.
      • Ruz M.
      • Arredondo M.
      Iron, copper, and zinc transport: inhibition of divalent metal transporter 1 (DMT1) and human copper transporter 1 (hCTR1) by shRNA.
      When iron is absorbed and ferritin increases, hepcidin binds to ferroportin, and ferroportin is internalized and degraded, leading to decreased export of cellular iron.
      • Anderson G.J.
      • Frazer D.M.
      • McLaren G.D.
      Iron absorption and metabolism.
      When a patient on hemodialysis is unable to maintain a target hemoglobin value (hemoglobin level of 100-120 g/L), despite erythropoiesis-stimulating agent treatment, if the patient has a serum ferritin level of <100 ng/mL (<224.7 pmol/L) and a transferrin saturation of <20%, iron supplement therapy is recommended.
      • Yamamoto H.
      • Nishi S.
      • Tomo T.
      • Masakane I.
      • Saito K.
      • Nangaku M.
      2015 Japanese Society for dialysis therapy: Guidelines for renal anemia in chronic kidney disease.
      Mean corpuscular hemoglobin is controlled to 30-35 pg, and if it is <30 pg, iron is replenished. The RBC count is controlled in the range of 300-350 (1012/L), and if it is <300 (1012/L), erythropoietin is considered to be insufficient and use of an erythropoiesis-stimulating agent is increased.
      • Tomosugi N.
      • Koshino Y.
      Tips for erythropoiesis-stimulating agent treatment of renal anemia.
      After iron has been pumped from ferroportin, hephaestin requires copper (Fig. 4, left). Iron is converted from the divalent to trivalent form by hephaestin and is carried by transferrin. Copper is a divalent copper ion, which has a pathway that competes with iron and zinc (mentioned above); it also has a pathway that involves reduction from the divalent to monovalent form, followed by absorption in the duodenum.
      • Prohaska J.R.
      • Gybina A.A.
      Intracellular copper transport in mammals.
      In the relationship between zinc and copper, absorption of copper is inhibited by induced metallothionein (a metal-binding protein in the Golgi apparatus
      ).
      • Suzuki K.T.
      • Maitani T.
      Metal-dependent properties of metallothionein. Replacement in vitro of zinc in zinc-thionein with copper.
      Metallothionein has the ability to bind to heavy metals via the thiol group of cysteine residues, which make up almost 30% of its constituents. Metallothionein plays a protective role against metal toxicity and oxidative stress, and is involved in the regulation of zinc and copper.
      • Suhy D.A.
      • Simon K.D.
      • Linzer D.I.
      • O'Halloran T.V.
      Metallothionein is part of a zinc-scavenging mechanism for cell survival under conditions of extreme zinc deprivation.
      Metallothionein is capable of binding 7 divalent (Zn2+) and up to 12 monovalent (Cu+) metal ions in vivo.
      • Kägi J.H.
      • Kojima Y.
      Chemistry and biochemistry of metallothionein.
      Metallothionein normally binds to zinc, but cadmium, mercury, and copper replace zinc because they have stronger binding strength. The molecular weight of metallothionein is approximately 6,500 Da and it is removed by hemodialysis.
      • Kägi J.H.
      Overview of metallothionein.
      Therefore, as zinc levels increase, iron and copper levels decrease (Fig. 4, middle). When replenishing zinc, careful monitoring is needed regarding zinc concentrations, as well as iron and copper concentrations.
      The most common clinical symptoms associated with copper deficiency include anemia, leukopenia, and bone lesions (scorbutic-like bone changes and occipital horn). When copper deficiency is suspected, the serum ceruloplasmin (Cp) level and the serum copper level should be measured. Except in newborns and small infants, serum Cp levels may be interpreted as follows: 10-20 mg/dL, mild decrease; 5-10 mg/dL, moderate decrease; and 5 mg/dL or less, marked decrease. And serum copper levels may be interpreted as follows: 60-80 μg/dL, mild decrease; 40-60 μg/dL, moderate decrease; 40 μg/dL or less, marked decrease.
      • Aoki T.
      Copper deficiency and the clinical Practice.
      Copper deficiency may occur when serum zinc concentrations exceed 250 μg/dL (38.23 μmol/L) after long-term administration of zinc.
      • Railey A.M.
      • Micheli T.L.
      • Wanschura P.B.
      • Flinn J.M.
      Alterations in fear response and spatial memory in pre- and post-natal zinc supplemented rats: remediation by copper.
      However, in patients on hemodialysis, copper deficiency occurs when serum zinc concentrations exceed 120 μg/dL (18.35 μmol/L). Therefore, reducing or discontinuing zinc supplementation is desirable if serum zinc concentrations exceed 120 μg/dL (18.35 μmol/L).
      • Takahashi A.
      Serum copper concentration after zinc supplementation for dialysis patients. [Japanese].
      Furthermore, in cases where serum zinc levels are ≥100 μg/dL (15.29 μmol/L) after zinc supplementation, most patients have copper deficiency after 3 months when zinc supplementation is continued (Fig. 5). Nishime reports a stricter recommendation that in the hemodialysis group, the upper limit of zinc to avoid copper deficiency is 109.7 μg/dL and the upper limit of safety is 78.3 μg/dL. He also recommends checking both zinc and copper values monthly after prescribing zinc acetate.
      • Nishime K.
      • Kondo M.
      • Saito K.
      • Miyawaki H.
      • Nakagawa T.
      Zinc burden evokes copper deficiency in the hypoalbuminemic hemodialysis patients.
      Figure thumbnail gr5
      Figure 5Scatter plot of serum zinc and copper concentrations after continuous administration of zinc acetate hydrate 50 mg/day.
      • Arnadottir M.
      • Gudnason V.
      • Hultberg B.
      Treatment with different doses of folic acid in haemodialysis patients: effects on folate distribution and aminothiol concentrations.
      Results of a retrospective study on serum zinc and copper concentrations in 36 outpatients on hemodialysis in the morning. The patients had serum zinc concentrations of <80 μg/dL (12.23 μmol/L) and were supplemented with zinc acetate 50 mg/day (17 men, 19 women, mean age: 69.6 ± 9.6 years). The approximate curve of the entire scatter plot intersects the lower limit of the normal serum copper concentration of 78 μg/dL (12.27 μmol/L) and serum zinc concentration of approximately 120 μg/dL (18.35 μmol/L).
      In the case of copper deficiency, recovery of serum copper concentrations is observed only by withdrawal of zinc acetate hydrate tablets. Therefore, when zinc supplementation is performed, serum concentrations of both zinc and copper should be measured at least every 3 months.
      If copper deficiency is observed, it should be treated with oral or intravenous copper replacement in the form of copper gluconate, copper sulfate, or copper chloride.
      • Myint Z.W.
      • Oo T.H.
      • Thein K.Z.
      • Tun A.M.
      • Saeed H.
      Copper deficiency anemia: review article.
      A total of 1.5-3 mg/day of copper is usually orally administered as copper sulfate. Because patients on hemodialysis with copper deficiency are often malnourished,
      • Collins J.F.
      Copper.
      intradialytic parenteral nutrition may be utilized to provide additional protein and energy.
      • Dukkipati R.
      • Kalantar-Zadeh K.
      • Kopple J.D.
      Is there a role for intradialytic parenteral nutrition? A review of the evidence.
      However, simultaneous administration of a trace element preparation is necessary to prevent copper deficiency.
      • Fuhrman M.P.
      • Herrmann V.
      • Masidonski P.
      • Eby C.
      Pancytopenia after removal of copper from total parenteral nutrition.
      The use of copper-containing dietary supplements is also an option. Foods high in copper levels include liver (12,400 μg per 3-ounce serving of beef liver), cocoa (938 μg per 2-ounce serving of unsweetened baking chocolate), potatoes (675 μg per medium potato), mushrooms (650 μg per half-cup serving of shiitake mushrooms), and nuts (629 μg per 1-ounce serving)
      • Collins J.F.
      Copper.
      ,
      National Institutes of Health
      Copper: Fact Sheet for health Professionals.
      ; because these foods are also sources of phosphorus and potassium,
      • Ros E.
      Health benefits of nut consumption.
      ,
      • Margier M.
      • Georgé S.
      • Hafnaoui N.
      • et al.
      Nutritional composition and bioactive content of legumes: characterization of pulses frequently consumed in France and effect of the cooking method.
      their consumption should be carefully considered to ensure safety in patients on hemodialysis. Many types of seafood (e.g., squid, octopus, shrimp, crab, and shellfish) are also rich in copper, since they use hemocyanin
      • Venugopal V.
      • Gopakumar K.
      Shellfish: nutritive value, health benefits, and consumer safety.
      (a copper-containing respiratory pigment in mollusks and arthropods
      • Coates C.J.
      • Costa-Paiva E.M.
      Multifunctional roles of hemocyanins.
      ) to carry oxygen instead of hemoglobin. When oral zinc supplementation is used, dietary guidance should focus on copper rather than zinc.

      Conclusions

      In patients on hemodialysis, serum zinc levels are often low, and proper zinc supplementation increases hemoglobin levels, leading to a reduction in erythropoiesis-stimulating agent prescriptions. It is important to understandhow zinc and copper act in the process of RBC hematopoiesis; it is also important to supplement zinc and copper when necessary. Because copper deficiency occurs when zinc is inappropriately supplemented, serum levels of both zinc and copper should be measured every few months. Before administering zinc, it is important to ensure that no copper deficiency is present. In patients with copper deficiency, copper supplementation should initially be performed, followed by treatment for zinc deficiency.

      Practical Application

      In patients on hemodialysis, serum levels of zinc and copper should be measured at intervals of ≤3 months. Careful monitoring is needed to prevent copper deficiency in patients receiving oral zinc supplementation. The use of intravenous zinc preparations can help to avoid zinc-induced copper deficiency.

      Author contributions

      A.T. was involved in conceptualization, design, original draft preparation, review, and editing of the manuscript. A.T. takes responsibility that this review has been reported honestly, accurately, and transparently, and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved.

      Acknowledgments

      The author thanks Ellen Knapp, PhD, and Ryan Chastain-Gross, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

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