81（41）Latent zinc deficiency and zinc
supplementation in hemodialysis
patientsTesuya Iwata１）, Miki Yamauchi２）, Yutaka Kuroiwa３）, Masanobu Okamoto４）, Sadami Nishi５）and Tatsuo Fukushima６）
１）Division of Medical Engineering, Nagasaki Prefectural Tsusima Izuhara Hospital２）Division of Internal Medicine, Nagasaki Prefectjral Tsusima Izuhara Hospital３）Division of Clinical Laboratory, Nagasaki Prefectjral Tsusima Izuhara Hospital４）Division of Hemodialysis Center, Nagasaki Prefectjral Tsusima Izuhara Hospital５）Shino-Test Corporation
６）FUKUSHIMA Medical Reseach Clinic

Abstract
The zinc supplementation therapy using Polaprezinc was evaluated for 32 patients
undergoing hemodialysis. Their serum zinc concentration was significantly improved（45 to70μg/dl）. Although their anemia level was not significantly changed（10.3 to 10.2 g/dl）,the Dolbepoietin α dosage to keep their hemoglobin 10 to 12g/dl was decreased（26.4 to19.2μg/week）. The reduced cost of Darbeopietin was estimated as 20,000Yen per person
per year in our facility. The zinc supplementation therapy is effective not only hematopoiesis
but also medical economy.

KEY WORDSZinc supplementation, Polaprezinc, CKD, Hemodialysis patients

Correspondence to：TESUYA IWATA ME
Division of Medical Engineering, NAGASAKI PREFECTURAL TSUSIMA IZUHARAHOSPITAL Mitsushimamachi Kechiotsu, Tsushima city, NAGASAKI, 817-0322 JAPANTEL +81-920-54-7111
FAX +81-920-54-7110

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Introduction
Renal anemia is one of the importantcomplications of Chronic Kidney Disease（CKD）,
especially in patients undergoing hemodialysis1,2）.

83（43）

at a dosage of 150mg/day which contains 34mg/

was obtained in writing; patients required zincplease write your feeling to take the tablet.

day of zinc was administered to‘with’group.

therapy due to zinc deficiency and they were２）Did your wound heal faster than before thec）Erythropoiesis Stimulating Agents (ESA)
In Tsushima Izuhara Hospital, to control theintended purpose, as gastric ulcer therapy.

patients anemia Dorbepoietin（rh-EPO）
was clinically introduced into therapy

used via intra-venous. And in this hospital, thefor renal anemia in patients with high stage

target anemia level is 10 to 12g/dl as theirsupplementation therapy. This questionnaire

CKD. However, there are still many patients

hemoglobin data at post hemodialysis sampling.

was consisted of five questions.

who are suffering from rh-EPO resistant anemia.

When their hemoglobin data was over 12g/dl,１） Could you take the tablet of Polaprezinc

Recently, Fukushima et al reported the highthe DA dosage was reduced as 20μg/weekly.

hemodialysis, and also the effect of zinctreatment? Yes, No or Neither.
３）Did your sense of taste improve? Yes, No orNeither.

g）Questionnaire

In 1980’s, recombinant human erythropoietin

prevalence of zinc deficient patients undergoingalfa（DA）in only

given zinc by using polaprezinc, not for its４） Did your appetite improved? Yes, No orWe prepared a questionnaire sheet for zincNeither.
５）If you feel another change in your feelingafter taking the tablet, please write.

easily? Yes or No, If your question is No,d）Fe agents

supplementation for renal anemia ３）. Indeed,

Their data about Fe kinetics including serum

hemodialysis patients have been found to have

Fe concentration, total iron binding capacitylow serum zinc concentration 4,5）. We evaluate（TIBC）and ferritin was measured every month.

here whether the zinc supplementation canT r a n s f e r r i n s a t u r a t i o n（ T S A T ）w a s a l s o

improve their serum zinc concentration and also

calculated as conventional formula. When either

anemia level.

TSAT was less than 20% or ferritin was lessthan 100μg/ml, the Fe supplementation was

Subjects & Methodsa）Patients
Thirty-two patients with chronic renal failuredone. The Fe supplementation was intravenously
infused 40mg of saccharated ferric oxide after
hemodialysis session one time per week.

e）Laboratory data

receiving outpatient maintenance hemodialysis

Their laboratory data including CBC, Fe（male：23, female：9, mean age：64. 34 years

kinetics parameters and serum zincold）those who were not taking zinc-based agentsconcentration was measured for 6 months. CBCand supplementation were screened to measureand biochemical data including mineral and renal

data combined blood count（CBC）, biochemical

failure associated data was measured two times

examination and serum levels of zinc and copper.

per month. Fe kinetics markers were measuredb）Zinc therapy and improvement of anemia

once a month. Serum Zn was measured in twopoints at the beginning and the end of this study.

Thirty-two chronic renal failure patients

The serum copper level was also investigated inreceiving hemodialysis at Tsushima Izuhara

this study because several patients wereHospital were randomly divided into two groups.

diagnosed as copper deficiency during zinc

The first group named‘with Zn’is composed ofsupplementation６）.

18 patients（male=12, female=6, mean age=62.5year-old）. The second group named‘without

Fig. 1 Serum Zinc concentrationsf）Ethical approval

Zn’ is consisted of 14 patients（ male=11,A following explanation was given to thefemale=3, mean age=66.7 year-old）. Polaprezinc

patients before polaprezinc therapy and consent

Fig. 2 Serum copper concentrations

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Result85（45）b）Copper concentration（Fig.2）a）Zinc concentration（Fig.1）
Fig. 1 shows the changes in the serum zincconcentration at the beginning and the end of zinc
supplementation. As seen in figure, serum zincconcentration was elevated 45μg/ml to 75μg/dl

Significant change in serum copper concentration was not seen in both groups（with：90 to 89μg/dl, without：82 to 80μg/dl）.

c）Serum Iron level (Fig. 3)
Serum Iron level tended to elevate in‘without‘without Zn’
than ‘with Zn’（with Zn：

beginning of this study in patients with zinc

10/18=55.6%, without Zn 10/14=71.4%, N.S.）.

supplementation. At end of this study, DAd）Hemoglobin concentration（Fig.4）

dosage in patients with zinc supplementation
was decreased to 19.2μg/week. In patients

Hemoglobin level didn’t change in bothwithout zinc supplementation, DA dosage wasgroups（with 10.3 to 10.2 g/dl, without 10.1 to27.9μg/week at the beginning of this study and10.3 g/dl）.

declined to 27.9μg/week at the end. The effecte）Dalbepoietin alpha (DA) dosage（Fig.5）of decreasing DA dosage was seen in patient（p<0.05）
in patients with zinc supplementation. InZn’（40 to 50μg/dl, N.S.）, though it didn’t

comparison with this, serum zinc concentration

change significantly in patients with zinc

To control patient’s hemoglobin level in thechanges of DA dosage. A decrease in DA dosage

was not changed in patients without zincsupplementation（39 to 42μg/dl, N.S.）. There arerecommended target range 10g/dl to 12g/dl, thewas mainly seen in first to third month of this.
supplementation（42μg/dl to 43μg/dl）

more patients with iron supplementation innecessary DA dosage was 26.4μg/week at thestudy.

with zinc supplementation. Fig.6 shows theFig. 3 Serum Iron concentrations

Fig. 5 Darbepoietin α dosages

Fig. 4 Hemoglobin concentrations

Fig. 6 Changes of dosage of DA

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201687（47）f）Questionnaire Sheet (Fig. 7)１） Could you take the tablet of Polaprezinc

Fig. 7-B Did you feel any changes for your taste?

T wenty-five% of patients answered yes.

elevate their zinc level into normal range, andpharyngeal incongruity（one case）, difficulty inalso improve their anemia level. With regard to

taking the tablet due to disabled hands.

anemia, their hemoglobin level was not changed,
their hemoglobin level in 10 to 12 g/dl waspatients answered No,24% patients werereduced 7.2μg/week. This amount of ESA isneither.

very little, but it’s very expensive. In Japanese３）Does your taste was improved?

medical situation, the cost for hemodialysis

Fourteen % of patients answered yes. 86% ofsession includes all kinds of medicines orpatients answered No.

necessary devices, for example ESA, iron agent,some prescribed medicine, dialyzer or dialysate.

F ifteen % of patients answered yes, 80%

As you may know, the lower costs make thepatients answered No,5% patients werehigher benefit so called money gain. The cost ofneither.

. Based on
DA is 1μg=240 Yen（approx. 2US$）５）If you feel another change in your feelingthese exchange and calculation, we have 18

after taking the tablet, please write. Therepatients with zinc supplementation, therefore

were three opinions. The first was‘ my18*240Yen/week=17280Yen（144US$）/monthcondition became well’. The second was‘I

could be saved. Surprisingly, 207360 Yen（1728

was glad to see improvement in my laboratoryUS$）can be saved overall.
Recently, the effectiveness of zinc
supplementation therapy has been reported. InFig. 7-D Did you feel your appetite improve?

Japanese medical scene, especially inDiscussion

hemodialysis field the zinc supplementation

The Japanese Society for Dialysis Therapy

therapyhas been recognizing one of the effectrecommends that the anemia management intherapy in general. On the other hand, copper

CKD patients especially in hemodialysis patients

deficiency anemia has been reported６）. Althoughshould be generally treated by rhEPO or iron

The mechanism of copper deficiency

therapy into target range 10 to 12 g/dl ofbeen clarified, Kanbe pointed out that copper７）

hemoglobin

Three ‘Yes’ were seen. Two patients answered "my condition became better". The other answer was "I was glad to improve mylaboratory data".

however, the necessary dosage of DA to keepTwenty-four % of patients answered yes, 52%data’. The third was‘I became very fine!’

Fig. 7-E Any another changes?

serum zinc concentration and anemia level weresimilar to previous study３）. Polaprezinc could４）Does your appetite was improved?

Fig. 7-C Did you feel your wound heal faster?

In this study, our results about the changes ofeasily?

２）Does your wound was healed fast?

Fig. 7-A Could you feel take Promac tablet easily?

９）
concept of the Zinc Deficiency Anemia（ZDA）.

. However, there is still an urgent

absorption is inhibited by saturated

has not
status ofneed of elucidating the etiology of refractory

zinc based on the theory of Irving-Williams

anemia with no response to ESA. At the sames serum
series 10,11）. In this study, the patient’time, it is anticipated that treatments for anemia

copper level was not changed after zinc

in CKD patients, in addition to ESA and ironsupplementation. All patients are in outpatient.

８）. We planned theThey can take a usual diet in their home, andpresent study based on result indicating thatthey are in good nutrition status. In thisdialysis patients have significantly decreased

nutritional condition, 34mg of daily zincserum zinc concentration 4,5）, and the disease

supplementation can be caused a risk of copper

products, will emerge

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deficiency.
In this study, we carried out a questionnaire

Questionnaire also disclosed improvement of
their general condition. Regarding with taste,

about taking Polaprezinc tablet. Polaprezinc iswound healing and appetite, there is few patients

originally an anti-gastric ulcer agent commercial

answered as improving. There is no patient who

name is Promac ®（ZERIA Pharmaceutical Co

complained any complications or replied asLtd, Tokyo）. In Japan, the zinc including anti-exacerbation. Therefore zinc supplementation

gastric ulcer agent is generally used. Polaprezinc

might be done safety. Moreover, some patients

can supply 34mg of zinc per day quantitatively,

who were taking Polaprezinc in this study felt

and easy to take as a tablet, on the other hand,

improving their general condition. The zincother zinc supplying agent as zinc sulfate

supplementation by Polaprezinc is effective,

hydrate is too stinking to take.

without severe complication. Therefore patients

In our questionnaire only one case complained

undergoing hemodialysis should bepharyngeal incongruity, it presents the easinessrecommended to measure serum zinc level andin taking this tablet. Also, major side effect wasin case of lower zinc level, zinc supplementation

not seen during zinc supplementation.

might be considered.

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１）Iseki K：Screening for renal disease, what can６）Rowin J, Lewis Sl：Copper deficiency

be learned from the Okinawa experience. Nephrolmyeloneuropathy and pancytopenia secondary to

Dial Tranplant 18：899-905, 2003

overuse of zinc supplementation. J Neurol２）Silverberg D, Dov Wexler 2, Blum M, Wallman

Neurosurg Psychiatry 76：750-751, 2005

Y, Iaina A：The cardio–renal anaemia syndrome：７）2015 JSDT Guideline for Renal Anemia indoes it exist? Nephrol Dial Tranplant 18（Supple）

Chronic Kidney Disease 49(2)：89-158, 2016ⅷ7-12, 2003

（Language in Japanese）

３）Fukushima T, Horike H, Fujiki S, Kitada S,８）Go AS, et al：Chronic Kidney Disease and theSasaki T, Kashihara N：Zinc deficiency anemia

risk of death, cardiovascular event andand effects of zinc therapy in maintenancehospitalization. New Engl J Med 351：1296-1305,

hemodialysis patients. Ther Apher Dial 13：213219. 2009
４）Zumkley H, Bertram HP, Lison A, Knoll O, Losse
H：Aluminum, zinc and copper concentrations inplasma in chronic renal insufficiency. Clin Nephrol
12：18-21, 1979５）Hosokawa S, Yoshida O：Effect of erythropoietin

2004９）Plasad A, et al：Syndrome of iron deficiency
anemia, hepatosplenomegary, dwarfism andgeophagia. Am J Med 313 532-546, 196110）Irving H M N H, Williams R J P：The stabilityof transition-metal complexes. J Chem Soc：3192–3210. 1953

（rHuEpo）on trace elements and quality of life
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Acknowledgement
We would like to thank for Ms. Risa Fukushima to correct of this article for English.