Oral Zinc Supplementation Reduces the Erythropoietin Responsiveness Index in Patients on Hemodialysis

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Abstract

Background: In hemodialysis (HD) patients, zinc depletion caused by inadequate intake, malabsorption, and removal by HD treatment leads to erythropoiesis-stimulating agent (ESA) hyporesponsiveness. This study investigated the effects of zinc supplementation in HD patients with zinc deficiency on changes in the erythropoietin responsiveness index (ERI). Methods: Patients on HD with low serum zinc levels (<65 μg/dL) were randomly assigned to two groups: The polaprezinc group (who received daily polaprezinc, containing 34 mg/day of zinc) ( n = 35) and the control group (no supplementation) ( n = 35) for 12 months. All the 70 patients had been taking epoetin alpha as treatment for renal anemia. ERI was measured with the following equation: Weekly ESA dose (units)/dry weight (kg)/hemoglobin (g/dL). Results: There were no significant changes in hemoglobin levels within groups or between the control and polaprezinc groups during the study period. Although reticulocyte counts were increased immediately after zinc supplementation, this change was transient. Serum zinc levels were significantly increased and serum copper levels were significantly decreased in the polaprezinc group after three months; this persisted throughout the study period. Although there was no significant change in the serum iron or transferrin saturation levels in the polaprezinc group during the study period, serum ferritin levels significantly decreased following polaprezinc treatment. Further, in the polaprezinc group, ESA dosage and ERI were significantly decreased at 10 months and nine months, respectively, as compared with the baseline value. Multiple stepwise regression analysis revealed that the change in the serum zinc level was an independent predictor of lowered ERI. Conclusions: Zinc supplementation reduces ERI in patients undergoing HD and may be a novel therapeutic strategy for patients with renal anemia and low serum zinc levels.

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Most cited references 27

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Interleukin-6 regulates the zinc transporter Zip14 in liver and contributes to the hypozincemia of the acute-phase response.

Tolunay Aydemir, Mitchell Knutson, Tomas Ganz … (2005)

Infection and inflammation produce systemic responses that include hypozincemia and hypoferremia. The latter involves regulation of the iron transporter ferroportin 1 by hepcidin. The mechanism of reduced plasma zinc is not known. Transcripts of the two zinc transporter gene families (ZnT and Zip) were screened for regulation in mouse liver after turpentine-induced inflammation and LPS administration. Zip14 mRNA was the transporter transcript most up-regulated by inflammation and LPS. IL-6 knockout (IL-6(-/-)) mice did not exhibit either hypozincemia or the induction of Zip14 with turpentine inflammation. However, in IL-6(-/-) mice, LPS produced a milder hypozincemic response but no Zip14 induction. Northern analysis showed Zip14 up-regulation was specific for the liver, with one major transcript. Immunohistochemistry, using an antibody to an extracellular Zip14 epitope, showed both LPS and turpentine increased abundance of Zip14 at the plasma membrane of hepatocytes. IL-6 produced increased expression of Zip14 in primary hepatocytes cultures and localization of the protein to the plasma membrane. Transfection of mZip14 cDNA into human embryonic kidney cells increased zinc uptake as measured by both a fluorescent probe for free Zn(2+) and (65)Zn accumulation, as well as by metallothionein mRNA induction, all indicating that Zip14 functions as a zinc importer. Zip14 was localized in plasma membrane of the transfected cells. These in vivo and in vitro experiments demonstrate that Zip14 expression is up-regulated through IL-6, and that this zinc transporter most likely plays a major role in the mechanism responsible for hypozincemia that accompanies the acute-phase response to inflammation and infection.

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Anemia as a risk factor for cardiovascular disease in The Atherosclerosis Risk in Communities (ARIC) study.

Mark J. Sarnak, Hocine Tighiouart, Guruprasad Manjunath … (2002)

We investigated whether the presence of anemia is a risk factor for cardiovascular disease (CVD) outcomes in the general population. Chronic anemia is a risk factor for CVD outcomes in patients with kidney disease and in patients with heart failure, but has not been evaluated as a risk factor in the general population. The Atherosclerosis Risk in Communities (ARIC) study was used to evaluate the relationship of anemia, defined by hemoglobin <13 g/dl in men and <12 g/dl in women, to CVD. Cox proportional hazards regression was used to adjust the relationship between anemia and CVD outcomes for other covariates in the entire study cohort, as well as in subgroups of men, women, African Americans and whites. A total of 14,410 subjects (6,267 men and 8,143 women) without CVD at baseline had hemoglobin levels measured. Three hundred men (4.8%) and 1,058 women (13.0%) were anemic. During an average follow-up of 6.1 years there was a total of 549 (3.8%) CVD events. The presence of anemia was independently associated with an increased risk of CVD (hazard ratio [95% confidence interval] of 1.41 [1.01, 1.95]) in the entire study cohort. In subgroup analyses the hazard ratios were in the same direction, although not statistically significant in all cases. Anemia is an independent risk factor for CVD outcomes in the ARIC cohort, a community cohort of subjects between the ages of 45 and 64 years.

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Substrate profile and metal-ion selectivity of human divalent metal-ion transporter-1.

Anthony C Illing, Ali Shawki, Christopher L Cunningham … (2012)

Divalent metal-ion transporter-1 (DMT1) is a H(+)-coupled metal-ion transporter that plays essential roles in iron homeostasis. DMT1 exhibits reactivity (based on evoked currents) with a broad range of metal ions; however, direct measurement of transport is lacking for many of its potential substrates. We performed a comprehensive substrate-profile analysis for human DMT1 expressed in RNA-injected Xenopus oocytes by using radiotracer assays and the continuous measurement of transport by fluorescence with the metal-sensitive PhenGreen SK fluorophore. We provide validation for the use of PhenGreen SK fluorescence quenching as a reporter of cellular metal-ion uptake. We determined metal-ion selectivity under fixed conditions using the voltage clamp. Radiotracer and continuous measurement of transport by fluorescence assays revealed that DMT1 mediates the transport of several metal ions that were ranked in selectivity by using the ratio I(max)/K(0.5) (determined from evoked currents at -70 mV): Cd(2+) > Fe(2+) > Co(2+), Mn(2+) ≫ Zn(2+), Ni(2+), VO(2+). DMT1 expression did not stimulate the transport of Cr(2+), Cr(3+), Cu(+), Cu(2+), Fe(3+), Ga(3+), Hg(2+), or VO(+). (55)Fe(2+) transport was competitively inhibited by Co(2+) and Mn(2+). Zn(2+) only weakly inhibited (55)Fe(2+) transport. Our data reveal that DMT1 selects Fe(2+) over its other physiological substrates and provides a basis for predicting the contribution of DMT1 to intestinal, nasal, and pulmonary absorption of metal ions and their cellular uptake in other tissues. Whereas DMT1 is a likely route of entry for the toxic heavy metal cadmium, and may serve the metabolism of cobalt, manganese, and vanadium, we predict that DMT1 should contribute little if at all to the absorption or uptake of zinc. The conclusion in previous reports that copper is a substrate of DMT1 is not supported.

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Author and article information

Journal

Journal ID (nlm-ta): Nutrients

Journal ID (iso-abbrev): Nutrients

Journal ID (publisher-id): nutrients

Title: Nutrients

Publisher: MDPI

ISSN (Electronic): 2072-6643

Publication date (Electronic): 15 May 2015

Publication date Collection: May 2015

Volume: 7

Issue: 5

Pages: 3783-3795

Affiliations

[1 ]Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, 30-1 Oyaguchi Kami-chou, Itabashi-ku, Tokyo 173-8610, Japan; E-Mails: kobayashihiroki2@ 123456gmail.com (H.K.); kokada@ 123456med.nihon-u.ac.jp (K.O.); haru_li_huang@ 123456yahoo.co.jp (R.T.); maruyama.noriaki@ 123456nihon-u.ac.jp (N.M.); souma.masayoshi@ 123456nihon-u.ac.jp (M.S.)

[2 ]Department of Nephrology, Meirikai Chuo General Hospital, 3-2-11, Higashijujou, Kita-ku, 114-0001 Tokyo, Japan; E-Mail: kikuchi5308@ 123456air.ocn.ne.jp

[3 ]Department of Nephrology, Keiai Hospital, 3-10-6, Mukaihara, Itabashi-ku, 173-0036 Tokyo, Japan; E-Mail: thiguchi@ 123456keiai-hospital.jp

Author notes

[* ]Author to whom correspondence should be addressed; E-Mail: abe.masanori@ 123456nihon-u.ac.jp ; Tel.: +81-3-3972-8111; Fax: +81-3-3972-8311.

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Publisher ID: nutrients-07-03783

DOI: 10.3390/nu7053783

PMC ID: 4446779

PubMed ID: 25988769

SO-VID: 2dfa759d-4847-4e7b-b535-d65ab9f56191

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This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/4.0/).

Oral Zinc Supplementation Reduces the Erythropoietin Responsiveness Index in Patients on Hemodialysis

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Most cited references 27

Interleukin-6 regulates the zinc transporter Zip14 in liver and contributes to the hypozincemia of the acute-phase response.

Anemia as a risk factor for cardiovascular disease in The Atherosclerosis Risk in Communities (ARIC) study.

Substrate profile and metal-ion selectivity of human divalent metal-ion transporter-1.

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