Role of vitamin D in oxidative stress modulation in end‐stage renal disease patients: A double‐blind randomized clinical trial

Abstract

Introduction
Oxidative stress is considered as important actor in uremia‐associated morbidity and mortality in hemodialysis (HD) patients. We aimed to evaluate the role of vitamin D supplementation on oxidative stress parameters in this group.

Methods
This double‐blind randomized clinical trial was conducted on HD patients who were randomly allocated into intervention (n = 40) or control groups (n = 38) for 10 weeks. Blood samples were taken before and at the end of the trial to measure serum 25‐hydroxyvitamin D (25(OH)D), malondialdehyde (MDA), glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD). Data were analyzed using SPSS, and P value <0.05 was considered to be statistically significant.

Findings
Out of the 78 patients with a mean age of 44.7 ± 13.0 years, 55.1% were men. At the commencement of the study, there was no difference with respect to serum 25(OH)D levels in our groups (P = 0.575), but during the study it was significantly elevated in the intervention group (18.1 ± 9.1 vs. 31.7 ± 12.9, P < 0.0001). Serum antioxidative enzymes activity (GPx, CAT, and SOD) had significantly increased after vitamin D supplementation in the intervention group (P < 0.05). Furthermore, MDA levels was significantly reduced only in the intervention group (31.7 ± 18.0 vs. 24.7 ± 7.7, P = 0.018).

Discussion
Regular consumption of vitamin D can increase the GPx, CAT, SOD, and reduce the MDA plasma levels in HD patients. Since no adverse effects of vitamin D supplementation was reported by the patients; hence, it can be prescribed for HD patients.

Full text

Hemodialysis International 2020
ORIGINAL ARTICLE
Role of vitamin D in oxidative stress
modulation in end-stage renal disease
patients: A double-blind randomized clinical
trial
Leila MALEKMAKAN,
1
Zeinab KARIMI,
1
Afshin MANSOURIAN,
2
Maryam PAKFETRAT,
1
Jamshid ROOZBEH
1
, Khojaste RAHIMI JABERI
1
1
Shiraz Nephro-Urology Research Center, Shiraz University of Medical Sciences, Shiraz and
2
Department
of Anesthesiology, Yasuj University of Medical Sciences, Yasuj, Iran
Abstract
Introduction: Oxidative stress is considered as important actor in uremia-associated morbidity
and mortality in hemodialysis (HD) patients. We aimed to evaluate the role of vitamin D supplemen-
tation on oxidative stress parameters in this group.
Methods: This double-blind randomized clinical trial was conducted on HD patients who were
randomly allocated into intervention (n= 40) or control groups (n= 38) for 10 weeks. Blood
samples were taken before and at the end of the trial to measure serum 25-hydroxyvitamin D
(25(OH)D), malondialdehyde (MDA), glutathione peroxidase (GPx), catalase (CAT), and superox-
ide dismutase (SOD). Data were analyzed using SPSS, and Pvalue <0.05 was considered to be
statistically significant.
Findings: Out of the 78 patients with a mean age of 44.7 13.0 years, 55.1% were men. At the
commencement of the study, there was no difference with respect to serum 25(OH)D levels in
our groups (P= 0.575), but during the study it was significantly elevated in the intervention
group (18.1 9.1 vs. 31.7 12.9, P< 0.0001). Serum antioxidative enzymes activity (GPx, CAT,
and SOD) had significantly increased after vitamin D supplementation in the intervention group
(P< 0.05). Furthermore, MDA levels was significantly reduced only in the intervention group
(31.7 18.0 vs. 24.7 7.7, P= 0.018).
Discussion: Regular consumption of vitamin D can increase the GPx, CAT, SOD, and reduce the
MDA plasma levels in HD patients. Since no adverse effects of vitamin D supplementation was
reported by the patients; hence, it can be prescribed for HD patients.
Keywords: Hemodialysis, oxidative stress, vitamin D
Correspondence to: M. Pakfetrat, Shiraz Nephro-Urology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
E-mail: pakfetratm@gmail.com, pakfetratm@sums.ac.ir
Disclosure of grants or other funding statement: The Vice-Chancellery of Research and Technology of Shiraz University of
Medical Sciences financially supported this study. Registration number: IRCT20181001041190N1. Registration date: May
25, 2019.
Conflict of Interest: The authors declare that they have no conflict of interest.
© 2020 International Society for Hemodialysis
DOI:10.1111/hdi.12849
1

INTRODUCTION
Chronic kidney disease (CKD) is a life-threatening health
problem, mainly in developing countries, such as Iran.
1–3
Oxidative stress, as an essential part of CKD, is induced by
increasing oxidant mediator duo to uremia, increased oxygen
metabolism, increased inflammatory factors, iron therapy,
dialysis procedure, lack of antioxidant vitamins and microel-
ements, malnutrition, and renal replacement therapy-related
factors (each HD session causes a 14-fold increased oxidative
stress levels).
4–11
Although oxidative stress occurs due to the
increased inflammatory response, low serum concentration
of 25-hydroxyvitamin D (25(OH)D) has been associated
with raised inflammation markers.
4
Vitamin D as a steroid hormone is known for its role in the
regulation of calcium, phosphorus, and bone metabolism. It
is 25-hydroxylated in the liver and then undergoes 1-alpha-
hydroxylation to its active form, 1,25-dihydroxyvitamin D
(1,25(OH)2D), by 1-alpha-hydroxylase in the kidney with
normal function.
11–13
Vitamin D effects have been confirmed
in several organs including the immune system as 1,25(OH)
2D inhibited the cytokine production.
4,14
Chronic inflamma-
tion and serum low 25(OH)D are common among CKD
patients, which is associated with poor outcomes.
11–18
The
etiologies of hypovitaminosis D or disturbed vitamin D
metabolism in end-stage renal disease (ESRD) are not clear,
but comprise of decreased glomerular filtration rate, limited
sunlight exposure, and reduced ultraviolet-B-induced vitamin
D synthesis in the skin.
15
Several studies indicated significant benefits from
direct exogenous antioxidants therapy in HD patients.
8,9
Also, another study showed that some mechanisms that
vitamin D might reduce inflammation were associated
with lower mortality and improved survival.
5,14–18
Currently, few randomized clinical trials have investigated
the impact of the correction of vitamin D level on inflamma-
tion in dialysis patients. Therefore, we designed this study
to determine the beneficial effect of vitamin D, as an exoge-
nous antioxidant, on oxidative stress modulation among
HD patients.
MATERIAL AND METHODS
Study design
This double-blind, randomized placebo-controlled trial
was performed in HD centers affiliated with Shiraz Univer-
sity of Medical Sciences, Iran, from August 2018 till
September 2019. Our main goal was to identify the effect
of vitamin D supplementation on oxidative stress parame-
ters in HD patients. The study was approved by the local
Ethics Committee of Shiraz University of Medical Sciences
(ethical code: IR.sums.REC.1397.927) and registered in
the Clinical-Trials.gov of IRCT20181001041190N1. It
was conducted in accordance with the Declaration of Hel-
sinki and Good Clinical Practice principles.
Participants
The sample size was calculated at 80 patients based on
Type I error of 5% and statistical power of 80%. During
the course of the study, two patients from the control
group quitted the study. We recruited adults 18 years old
or older. They received 4-hour HD treatments three times
per week at least for 3 months, Kt/V> 1.2, administering
no other antioxidant medications, except for Nephrovit tab-
let (Nephrovit
®
OSVAH Pharmaceutical Company, Tehran,
Iran) with a dose of one tablet per day. Each Nephrovit tab-
let contain vitamin C (ascorbic acid 60 mg), niacin (niacin-
amide 20 mg), pantothenic acid (10 mg), vitamin B6
(pyridoxine hydrochloride 10 mg), vitamin B2 (riboflavin
1.7 mg), vitamin B1 (thiamine mononitrate 1.5 mg), folic
acid (5 mg), biotin (D-biotin 300 μg), and vitamin B12
(cyanocobalamin 6 μg). Patients were excluded, if they were
≥60 years old, had a mental or physical illness (such as
active infection, heart disease, severe depression, speech
impairment, and hearing loss), candidates for kidney trans-
plantation, used other complementary therapies, and could
not tolerate the drug in oral form. All patients provided a
written informed consent before their enrolment.
Randomization and masking
We recruited 78 patients who met the study inclusion
criteria, and then randomly allocated them into two groups
of intervention or vitamin D (n= 40) and control or placebo
(n= 38), using permutation block randomization for alloca-
tion sequence, utilizing 20 blocks of 4. The participants,
researchers, and the staff involved in patient’s treatment
were blinded to the group selection. All vitamin D and pla-
cebo pills were similar in size, shape, weight, color, and
identical in appearance. Pills were purchased from the
Zahravi Pharmaceutical Company (Tehran, Iran). Each
patient was given an order number and received the medica-
tions in the corresponding prepacked packets.
Procedures
Each patient in the intervention group received one pill
of oral vitamin D3 50 000 IU (D-Vitin
®
Zahravi Pharma-
ceutical Company) every week for 10 weeks. Likewise,
the control group received placebo at the same time.
Specification and amount of drug doses remained
Malekmakan et al.
2Hemodialysis International 2020

constant throughout the study. Also, all patients in both
groups received Nephrovit tablet as it was prescribed in
their regimen. All patients had arteriovenous fistula and
they had the membrane and the general dialysis prescrip-
tion was similar for all patients.
Data collection
First, information including age, gender, cause of kidney
failure, underlying diseases, duration of dialysis, and medi-
cations was recorded. Each patient blood sample was
taken just before and at the end of the trial from the arte-
rial line immediately before heparin administration in mid-
week dialysis session. For all patients, blood samples were
drawn to measure the serum level of 25(OH)D, blood urea
nitrogen (BUN), creatinine (Cr), and oxidative stress indi-
ces as plasma malonyldialdehyde (MDA); and also
antioxidative enzymes activity including glutathione perox-
idase (GPx), catalase (CAT), and superoxide dismutase
(SOD). The samples were immediately centrifuged and fro-
zen at −80C before the measurements.
Biochemical measurements
Serum Cr and BUN levels were measured by an
autoanalyzer at Nemazi Hospital Laboratory, Shiraz (RA-
1000 Technicon; Tarrytown, New York, USA). Serum
25(OH)D quantification was done by the 25-OH Vitamin D
ELISA Kit (Padtan Gostar Isar Co., Tehran, Iran, 1.98
ng/mL sensitivity). Results are expressed as ng/mL. Based
on 25(OH)D levels, vitamin D status was classified into
deficiency (<20 ng/mL), insufficiency (21 < ng/mL < 29),
and sufficiency (>30 ng/mL).
19
We assessed oxidative
markers in the serum samples by microplate reader
(Biotek, Winooski, VT; EPOCH2TC). MDA level of serum
samples was measured by thiobarbituric acid reactive sub-
stances assay method. The MDA level was measured at
532 nm, using microplate reader. SOD activity was evalu-
ated according to the Zell Bio Kit (Georgia, Germany, cat.
no.: ZB-SOD 48A) protocol at 420 nm for 2 minutes.
CAT activity was measured, using Aebi method. Hydrogen
peroxide (H
2
O
2
10%) is a CAT substrate and CAT activity
was measured at 240 nm for 2 minutes. The Fecondo and
Augustyn method was used to assess GPx activity. The
mixture consisted of ethylenediaminetetraacetate, nicotin-
amide-adenine dinucleotide phosphate (NADPH), glutathi-
one reductase, and sodium azide. There was a reduction
in the absorption of NADPH at 340 nm in microplate
reader for 10 minutes.
19–21
Statistical analysis
Data were analyzed, using SPSS-18 for windows.
Chi-square was used to assess the relationship between
the two qualitative data, and independent ttest and
paired ttest were employed to evaluate the correlation of
a quantitative data. Pvalue <0.05 was considered to be
statistically significant.
RESULTS
We recruited 78 patients with a mean age of 44.7 13.0,
and 55.1% of the patients were men (43 cases). The most
common causes of ESRD were diabetes mellitus (28.2%,
Table 1 Comparison of the demographic features between the trial and control patients
Variable
Groups
Pvalue
Intervention
a
,n= 40 Control, n=38
Age (years), mean ± SD 44.1 ± 13.4 45.3 ± 12.7 0.683
Sex (men), n(%) 22 (55.0) 21 (55.3) 0.981
Renal failure duration (years), mean ± SD 11.4 ± 12.3 6.9 ± 7.9 0.061
Renal failure cause, n(%)
Hypertension 11 (27.5) 10 (26.3)
Diabetes mellitus 8 (20.0) 14 (36.8) 0.327
Unknown 4 (10.0) 4 (10.5)
Others 17 (42.5) 10 (26.3)
Dialysis duration (years), mean ± SD 7.1 ± 14.2 4.4 ± 5.7 0.285
Kt/V, mean ± SD 1.5 ± 0.3 1.3 ± 0.2 0.185
BUN (mg/dL) 31.6 ± 10.9 35.4 ± 21.9 0.343
Cr (mg/dL) 4.6 ± 1.9 5.1 ± 3.5 0.203
a
Vitamin D group.
BUN = blood urea nitrogen; Cr = creatinine; Kt/V= quantify dialysis treatment adequacy; n= number.
Vitamin D and oxidative stress
Hemodialysis International 2020 3

22 patients) and hypertension (26.9%, 21 patients).
The mean Kt/Vat the initiation and end of the study were
1.4 and 1.3, indicating efficient dialysis (P= 0.185).
Our patients were divided into two groups: interven-
tion (n= 40) and control group (n= 38). Table 1 shows
our patients demographic information. As shown, there
Table 2 Comparison of the plasma 25-hydroxyvitamin D between the trial and control groups
25-hydroxyvitamin D (ng/mL), mean ± SD
Groups
Pvalue
Intervention
a
,n= 40 Control, n=38
Deficiency
Baseline 31 (77.5) 28 (73.7) 0.794
End of study 13 (32.5) 24 (63.2) 0.012
Insufficiency
Baseline 9 (22.5) 2 (5.3) 0.362
End of study 4 (10.0) 0 (0.0) 0.002
Sufficiency
Baseline 5 (12.5) 8 (21.0) 0.239
End of study 18 (45.0) 14 (36.8) 0.498
25-Hydroxyvitamin D
Baseline 18.1 ± 9.1 19.8 ± 16.6 0.575
End of study 31.7 ± 12.9 24.9 ± 20.6 0.087
Pvalue <0.0001 0.192 –
Ratio 13.6 ± 12.7 5.1 ± 14.5 0.008
a
Vitamin D group.
Ratio = after–before value.
Table 3 Comparison of the oxidative parameters between the trial and control patients
Variable, mean ± SD
Groups
Pvalue
Intervention
a
,n= 40 Control, n=38
MDA (IU/mg)
Baseline 31.7 ± 18.0 36.6 ± 17.4 0.222
End of study 24.7 ± 7.7 32.3 ± 9.3 <0.0001
Pvalue 0.018 0.080 –
Ratio 7.0 ± 7.9 4.3 ± 5.2 0.475
CAT (IU/mg)
Baseline 3.3 ± 1.9 4.2 ± 3.2 0.128
End of study 5.9 ± 7.4 3.6 ± 2.3 0.071
Pvalue 0.033 0.442 –
Ratio 2.6 ± 7.5 −0.5 ± 4.3 0.025
GPx (IU/mg)
Baseline 1.6 ± 1.7 2.6 ± 3.5 0.115
End of study 18.4 ± 20.3 2.9 ± 2.7 <0.0001
Pvalue <0.0001 0.537 –
Ratio 16.7 ± 19.6 0.3 ± 2.7 <0.0001
SOD (IU/mg)
Baseline 15.1 ± 6.6 13.4 ± 7.0 0.286
End of study 23.7 ± 9.7 12.3 ± 7.7 <0.0001
Pvalue <0.0001 0.151 –
Ratio 8.5 ± 13.1 −1.1 ± 4.6 <0.0001
CAT = catalase activity; GPx = glutathione peroxidase activity; MDA = plasma malonyldialdehyde; Ratio = after–before value; SOD = superox-
ide dismutase.
a
Vitamin D group.
Malekmakan et al.
4Hemodialysis International 2020

was no significant difference in the baseline data of the
two groups at the beginning of the study (P> 0.05). The
mean age in the intervention and control groups was
44.1 13.4 and 45.3 12.7 (P= 0.683). In total,
55.0% (22 patients) in the intervention and 55.3%
(21 patients) in the control group were men (P= 0.981).
The mean serum level of BUN and Cr at the beginning of
the study was 31.6 10.9 and 4.6 1.9 for the inter-
vention and 35.4 21.9 and 5.1 3.5 for the con-
trols (P> 0.05).
The prevalence of hypovitaminosis D in our patients was
evaluated as follows: 75.3% of the patients (58 cases) had
25(OH)D deficiency, 8.9% (7 cases) had insufficiency, and
16.9% (13 cases) had sufficient vitamin D. As shown in
Table 2, there was no difference in the serum level of
25(OH)D among the two groups at the beginning of the
study (18.1 9.1 vs. 19.8 16.6, P= 0.575), while during
the study, it significantly increased in the intervention group
(18.1 9.1 vs. 31.7 12.9, P< 0.0001). However, there
was no significant change in the serum level of 25(OH)D in
the control group (22.3 20.5 vs. 24.9 16.0, P= 0.192).
On the other hand, at the end of the treatment, 25(OH)D
serumlevelwashigherintheinterventiongroupincompari-
son with the control group, but was not significant
(P= 0.087). Also, the change of 25(OH)D level in the inter-
vention group was significantly higher than the control
group (13.5 12.7 vs. 5.1 4.5, P=0.008).
None of the patients reached hypervitaminosis D level
during the study. At the end of the study, some oxidative
activities were compared among the two groups, as
shown in Table 3. All the serum levels of anti-oxidative
enzymes activity, including GPx, CAT, and SOD, had
significantly increased in the intervention group
(P< 0.05), while these assessments did not significantly
change in the control group (P> 0.05). The change in
the enzymes activity during the study was significantly
higher in the intervention group in comparison with the
control group (P< 0.05).
Moreover, the plasma level of MDA, as an oxidative
stress product, significantly decreased in the intervention
group (31.7 18.0 vs. 24.7 7.7, P= 0.018 compared
to 36.6 17.4 vs. 32.3 9.3, P= 0.080). MDA change
during the study was higher in the intervention group in
comparison with the control group, but it was not signif-
icant (7.0 7.9 vs. 4.3 5.2, P= 0.475).
DISCUSSION
CKD as a global health problem is associated with a high
prevalence of oxidative stress. In addition to formation of
pro-oxidant molecules, antioxidant mechanisms are
affected by malnutrition, dietary restrictions and poor
intake of antioxidants including vitamins D.
11
Vitamin D
deficiency is considered as public health concern, which
is very frequent in CKD.
22,23
Considering vitamin D sup-
plementation is definitely important and debated in CKD
patients.
11,22,23
We revealed a high frequency of hypovitaminosis D
(83.1%) in our HD population. In this clinical trial, we
showed that vitamin D levels were low at baseline, and
treatment with vitamin D supplementation for 10 weeks
was effective in restoring the vitamin D status and for
improving the oxidative stress modulation in HD
patients. In line with our results, other studies showed
that vitamin D was low among CKD patients.
22–27
Similar to our results, other studies showed that
vitamin D level significantly increased after vitamin D
supplementation while vitamin D level did not signifi-
cant changed in the control group.
4,12,14,22,24
How-
ever, some studies did not find any difference in
25(OH)D after treatment, and concluded that it might
be have been duo to inability to reach sufficient
25(OH)D levels, and modification of lifestyle and
habits should be considered.
26
Another study con-
cluded that HD patients had insufficient 24,25-
dihydroxycholecalciferol production in spite of having
sufficient 25(OH)D levels. This is most likely the
destructive effect of CYP24A1 enzyme suppression.
12
There is no agreement on the optimal level of 25(OH)D
among CKD patients, selected type of vitamin D supple-
ment, and dosage; so, we still refer to the optimal level
of general population. Although there are some guide-
lines, further investigation is warranted.
23
Since vitamin
D has several benefits and few side effects, its prescrip-
tion should be recommended for these patients.
22
OXIDATIVE STRESS AND
INFLAMMATION
It is apparent that oxidative stress and inflammation
contribute to the development of CKD.
6–8
It was
reported that antioxidant enzymes increase after HD,
and oxidation markers decrease.
24
Vitamin D therapy
can effectively modulate the oxidative stress and
inflammation.
17,18,22
Our results suggest that treatment with vitamin D has
antioxidant effects on HD patients. All of the serum levels
of antioxidative enzymes activity in the current study,
including GPx, CAT, and SOD, had significantly
increased in the intervention group compared to the con-
trol group. Moreover, the MDA level, as an oxidative
stress product was significantly reduced.
Vitamin D and oxidative stress
Hemodialysis International 2020 5

Similar to our results, Izquierdo et al. reported that the
CAT and SOD activity significantly increased, while
MDA significantly decreased after paricalcitol treatment
in HD patients.
17
Also, Tajbakhsh et al. showed that
serum GPx, CAT, and SOD significantly increased after
vitamin D supplementation in the HD group.
24
Another
study revealed that treatment of HD patients via intrave-
nous calcitriol could improve the oxidative stress, while
SOD activities remained unchanged.
28
Another study on
HD patients showed that CAT and SOD activity was sig-
nificantly up-regulated after treatment with paricalcitol
treatment, and MDA plasma was significantly reduced.
11
Nasif et al. reported that calcitriol therapy could effec-
tively increase the SOD among HD patients.
18
Wu et al.
indicated that vitamin D suppressed several inflammatory
markers in HD patients.
16
Similarly, Tanaka et al.
showed that intravenous calcitriol not only decreased the
accumulation of free radicals but also strengthened
endogenous antioxidant activity in HD.
28
Restoration of dialysis patients’vitamin D status trig-
gered CYP27B1 upregulation and vitamin D receptor
(VDR) expression in the monocytes, so decreased the cir-
culating inflammatory markers. The increased expression
of CYP27B1 and VDR indicated that cholecalciferol sup-
plementation positively regulated vitamin D-regulatory
proteins in the monocytes.
4
It seems that VDR decreases
the oxidative stress by inhibiting the renin–angiotensin
system, which is a powerful modulator of the immune
response.
28
In addition, vitamin D supplementation
among HD patients had beneficial effects on few gene
expressions related to inflammation and oxidative stress.
5
This study was conducted in a short duration, which
limits the results to short-term vitamin D effects in HD
patients. However, this is typical of a randomized
double-blind placebo-controlled study.
In conclusion, this study revealed the possible efficacy
and safety of vitamin D in oxidative stress modulation in
ESRD patients. Further studies with larger sample size
and longer duration are necessary to assess the impact of
the vitamin D on oxidative stress modulation among
these patients.
ACKNOWLEDGEMENT
The Vice-Chancellery of Research and Technology of
Shiraz University of Medical Sciences financially
supported this study. This article is based on a research
project with No 7791. The authors declare that they have
no conflict of interest. The authors wish to thank Mr
H. Argasi at the Research Consultation Center (RCC) of
Shiraz University of Medical Sciences for his invaluable
assistance in editing this manuscript.
AUTHOR CONTRIBUTIONS
Leila Malekmakan contributed to the design and data
analysis, drafted the manuscript, did the final approval,
and accepted the accountability for the overall work.
Zeinab Karimi and Afshin Mansourian contributed to the
design and data analysis, revised the manuscript, did the
final approval, and accepted accountability for the overall
work. Maryam Pakfetrat, Jamshid Roozbeh, and Khojaste
Rahimi Jaberi contributed to data collection, revised the
manuscript, did the final approval, and accepted
accountability for the overall work.
Manuscript received February 2020; revised May 2020;
accepted May 2020.
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