See corresponding editorial on page 1164.

Downloaded from https://academic.oup.com/ajcn/article/108/6/1342/5239885 by guest on 28 October 2020

Severe vitamin D deficiency is a risk factor for renal hyperfiltration
Jong Hyun Jhee,1 Ki Heon Nam,2 Seong Yeong An,2 Min-Uk Cha,2 Misol Lee,2 Seohyun Park,2 Hyoungnae Kim,2
Hae-Ryong Yun,2 Youn Kyung Kee,2 Jung Tak Park,2 Seung Hyeok Han,2 Shin-Wook Kang,2,3 and Tae-Hyun Yoo2
1 Divisionof Nephrology and Hypertension, Department of Internal Medicine, Inha University College of Medicine, Incheon, Korea; 2 Department of Internal
Medicine, College of Medicine, Institute of Kidney Disease Research; and 3 Department of Internal Medicine, College of Medicine, Severance Biomedical
Science Institute, Brain Korea 21 PLUS, Yonsei University, Seoul, Korea

ABSTRACT diabetic patients (1–3). RHF may cause glomerular hypertension,

Background: Vitamin D deficiency is associated with renal progres-
sion in chronic kidney disease. Moreover, improvement of clinical
outcomes after vitamin D supplementation has been reported in the
diabetic and chronic kidney disease population.
Objective: We investigated the association between renal hyperfiltra-
tion (RHF) and vitamin D status in a relatively healthy population.
Design: Data were retrieved from the Korean NHANES, a nation-
wide population-based cross-sectional study from 2008 to 2015.
Overall, 33,210 subjects with normal renal function were included
in the final analysis. Severe vitamin D deficiency was defined as
serum 25-hydroxyvitamin D concentration <10 ng/mL. RHF was
defined as estimated glomerular filtration rate with residual in the
>95th percentile after adjustment for age, sex, height, weight, and
history of hypertension or diabetes.
Results: The mean ± SD age of subjects was 48.1 ± 15.9 y, and the
number of women was 18,779 (56.5%). Estimated glomerular filtra-
tion rate was negatively associated with serum 25-hydroxyvitamin D
concentrations in multivariable linear regression analysis (β: −0.02;
95% CI: −0.02, −0.01; P < 0.001). Furthermore, 1637 (4.9%)
subjects were categorized into the RHF group, and the prevalence
of RHF was significantly higher in the severe vitamin D deficiency
group than in the sufficiency group (5.8% compared with 5.0%,
P < 0.001). In a multivariable logistic regression model, severe
vitamin D deficiency was a significant risk factor for RHF (OR: 2.41;
95% CI, 1.72, 3.43; P < 0.001).
Conclusions: Severe vitamin D deficiency is significantly associated
with increasing prevalence of RHF in a relatively healthy adult
population. Am J Clin Nutr 2018;108:1342–1351.
Keywords: Vitamin D deficiency, renal hyperfiltration, glomerular
hyperfiltration, chronic kidney disease
INTRODUCTION
Renal hyperfiltration (RHF) is a known risk factor for
chronic kidney disease (CKD) progression in hypertensive and
subsequent glomerulosclerosis, and finally loss of renal function
(1). RHF is also known to be associated with an increased risk of
all-cause and cardiovascular mortality in a relatively healthy adult
population as well as in diabetic patients (4). Recent clinical trials
have revealed that sodium-glucose co-transporter 2 inhibitors
mitigate glomerular hyperfiltration, and subsequently improve
albuminuria and composite renal outcomes in diabetic patients
(5). Medical conditions, including diabetes, hypertension, and
obesity, and lifestyle factors, such as smoking and lack of
physical activity, are reported to be associated with RHF (6–10).
However, the exact mechanism or cause of RHF remains unclear.
Vitamin D deficiency has been implicated in bone, cardiovas-
cular, and renal health and diseases (11–13). Conventionally, low
vitamin D concentrations are directly associated with impaired
bone metabolism, resulting in increased risk of bone fractures
(14). Over the past decades, expression of the vitamin D receptor
has been demonstrated in most tissues and cells in the body
The epidemiologic data used in this study were obtained from the Korea
NHANES (KNHANES IV, V, and VI) from 2008 to 2015, Republic of Korea.
This study was supported by a research grant from Inha University Hospital.
The funding source had no role in the conception of the study or the collection,
analysis, and interpretation of the data; writing of the manuscript; or the
decision to submit for publication.
Supplemental Tables 1–4 and Supplemental Figures 1–3 are available from
the “Supplementary data” link in the online posting of the article and from the
same link in the online table of contents at https://academic.oup.com/ajcn/.
Address correspondence to T-HY (e-mail: yoosy0316@yuhs.ac).
Abbreviations used: CKD, chronic kidney disease; eGFR, estimated
glomerular filtration rate; GFR, glomerular filtration rate; IRB, Institutional
Review Board; KNHANES, Korean NHANES; PSM, propensity score
matching; PTH, parathyroid hormone; RAAS, renin-angiotensin-aldosterone
system; RAS, renin angiotensin system; RHF, renal hyperfiltration; SBP,
systolic blood pressure.
Received March 23, 2018. Accepted for publication July 18, 2018.
First published online December 12, 2018; doi: https://doi.org/10.1093/
ajcn/nqy194.

1342 Am J Clin Nutr 2018;108:1342–1351. Printed in USA. © 2018 American Society for Nutrition. All rights reserved.
 VITAMIN D DEFICIENCY AND RENAL HYPERFILTRATION
(15), indicating that vitamin D also has extraskeletal effects.
Vitamin D also plays pleotropic roles in decreasing the risk
of several chronic illnesses, including cancers, autoimmune
diseases, infectious diseases, and cardiovascular disease (16–18).
Notably, vitamin D deficiency is known to be associated with an
increased risk of adverse clinical outcomes in patients with CKD
(19, 20). Conversely, decreased renal function is associated with
a reduced synthesis of 1,25-dihydroxyvitamin D, the active form
of vitamin D, and consequently results in disease progression
(21). Moreover, the renoprotective effects of vitamin D have
been demonstrated in human clinical trials. Oral vitamin D or
vitamin D analog supplementation enhanced the antiproteinuric
effects of the renin angiotensin system (RAS) inhibitors and
reduced albuminuria in patients with diabetic nephropathy and
IgA nephropathy (22, 23). Previous experimental studies have
suggested that an additive RAS inhibitory effect increases the
beneficial effects of vitamin D (24). Since intrarenal RAS
activation is a possible mechanism of RHF, we speculated that
vitamin D status is associated with RHF. Although the interaction
between vitamin D deficiency and CKD is well elucidated,
the relationship between vitamin D deficiency and glomerular
filtration rate (GFR) remains unclear in the general population.
In order to elucidate the impact of vitamin D deficiency
on RHF as a candidate in renal hemodynamic disturbances,
this study investigated the association between age-, sex-,
hypertension-, and diabetes-adjusted RHF, and vitamin D de-
ficiency within a large community-based cohort consisting of
relatively healthy adults.
METHODS
Study subjects
This study was based on data from the 4th , 5th , and 6th editions
of the Korean NHANES (KNHANES IV, V, and VI, 2008–
2015). KNHANES is a nationwide, population-based, and cross-
sectional health examination and survey regularly conducted by
FIGURE 1 Study subjects. KNHANES, Korean NHANES; 25(OH)D3, 25-hydroxyvitamin D3.
1343
the Division of Chronic Disease Surveillance of the Korea Cen-
ters for Disease Control and Prevention of the Ministry of Health
and Welfare to monitor the general health and nutrition status
of South Koreans (19). The KNHANES is composed of demo-
graphic, anthropometric, nutritional, and personal medical his-
tory data collected by trained investigators. A sampling frame was
developed based on multistage probability stratified according to
geographic location, sex, and age. Each KNHANES consists of
independent sets of participants from the South Korean popula-
tion. All participants were randomly selected from 600 randomly
selected districts of cities and provinces in South Korea.
Participants in KNHANES IV–VI were screened for this study.
A total of 53,105 subjects were initially screened and participants
<18 y old or with missing data were excluded. Given the aim of
Downloaded from https://academic.oup.com/ajcn/article/108/6/1342/5239885 by guest on 28 October 2020
the study, participants with an estimated glomerular filtration rate
(eGFR) <60 mL · min–1 · 1.73 m–2 were also excluded. Overall,
33,210 subjects were included in the final analysis. Eligible sub-
jects were categorized into 4 groups according to vitamin D con-
centrations (<10, 10–19.9, 20–29.9, and ≥30 ng/mL; Figure 1).
All participants in KNHANES provided their written informed
consent before the study began. KNHANES was approved by
the Institutional Review Board (IRB) of the Centers for Disease
Control and Prevention in Korea (KNHANES 2008–2014
IRB approvals 2008-04EXP-01-C, 2009-01CON-03-2C, 2010-
02CON-21-C, 2011-02CON-06C, 2012-01EXP-01-2C, 2013-
07CON-03-4C, and 2013-12EXP-03-5C; IRB approval was not
required for KNHANES 2015 because this survey was conducted
for the purpose of public welfare).
Anthropometric and laboratory data
Anthropometric measurements were obtained by trained ex-
perts following standardized protocols. The BMI was calculated
as weight (kg) divided by the square of height (m2 ). Activity
restriction was determined if the subject answered “yes” when
questioned whether they had any problems associated with daily
1344 JHEE ET AL.
physical activity. Systolic blood pressure (SBP) was measured
twice on the right arm at 5-min intervals using a standard mercury
sphygmomanometer (Baumanometer; Baum) and recorded as
average values. Hypertension was defined as SBP ≥140 mm Hg,
diastolic blood pressure ≥90 mm Hg, use of antihypertensive
medications, or previous diagnosis by a physician. Diabetes
mellitus was defined as serum fasting blood glucose ≥126 mg/dL,
use of antidiabetic medication, or previous diagnosis by a
physician.
Blood samples were collected after an ≥8-h fast and were
transported to a central laboratory within 24 h. Serum 25-
hydroxyvitamin D [25(OH)D] concentration and ferritin were
determined by radioimmunoassay (DiaSorin Inc.) using a γ -
counter (1470 Wizard; PerkinElmer). The interassay coefficient
of variation was 2.8–6.2%. The 25(OH)D concentration of
all samples was measured by the same institute to minimize
analytic variations. Vitamin D deficiency was defined as a
serum 25(OH)D concentration <20 ng/mL and severe vitamin
D deficiency as <10 ng/mL based on Endocrine Society
clinical practice guidelines (25). Moreover, serum 25(OH)D
concentrations between 20 and 29.9 ng/mL were defined as
vitamin D insufficient, whereas concentrations ≥30 ng/mL were
defined as sufficient. The Institute of Medicine of the National
Academy of Sciences also suggest guidelines for defining vitamin
D status. According to these guidelines, vitamin D deficiency is
defined as a serum 25(OH)D concentration <12 ng/mL, vitamin
D insufficiency as 12–20 ng/mL, and vitamin D sufficiency as
≥20 ng/mL (26). We adopted the Endocrine Society clinical
practice guidelines for the study analysis. Serum creatinine was
determined by a rate-blanked compensated Jaffe kinetic method
using Roche reagent CREA (Roche, Basel, Switzerland) and
a Roche CFAS calibrator, which had been calibrated against
an isotope dilution mass spectrometry reference method, on
a Hitachi Automatic Analyzer (Hitachi, Tokyo, Japan). We
checked the accuracy of the creatinine values through full
participation in the proficiency testing regimes of both the
College of American Pathologists CHM and the LN24 Creatinine
Accuracy Calibration Verification/Linearity progams, as well as
in the Korean External Quality Assurance Scheme. Acceptable
proficiency testing results were obtained for the study years
(27, 28). Blood hemoglobin concentrations were measured by
the sodium lauryl sulfate hemoglobin method. Urinalysis was
performed (Urisys 2400; Roche, Germany) and proteinuria
was defined as ≥1+ by dipstick test. The concentrations of
fasting plasma glucose, glycated hemoglobin, total cholesterol,
HDL cholesterol, LDL cholesterol, and alkaline phosphatase
were measured by an enzymatic method (Automatic Analyzer
7600; Hitachi). A chemiluminescence immunoassay (N-tact PTH
assay; DiaSorin) was used to measure serum-intact parathyroid
hormone (PTH). The average value of the interassay coefficient
of variation for the PTH assay was 8.0%.
Definition of RHF in healthy subjects
RHF was defined as previously suggested with some modifi-
cations (29). Briefly, the residuals were calculated from a multi-
variable linear regression analysis, where logarithm-transformed
eGFR was a dependent variable and logarithm-transformed age,
sex, height, weight, and history of hypertension or diabetes
were independent variables. A logarithm-transformed eGFR
>95th percentile after adjustment for logarithm-transformed age,
sex, height, weight, and history of hypertension or diabetes
was defined as RHF. The eGFR was calculated from the
Korean version of the Chronic Kidney Disease Epidemiology
Collaboration equation (30, 31).
Statistical analysis
All statistical analyses were performed with IBM SPSS
software for Windows version 23.0 (IBM Corporation, Armonk,
NY) and R software 3.3.1 (http://www.R-project.org). Contin-
uous variables are expressed as mean ± SD or median (IQR),
and categoric variables as absolute numbers with percentages.
Comparisons between groups were made using ANOVA or
Downloaded from https://academic.oup.com/ajcn/article/108/6/1342/5239885 by guest on 28 October 2020
Student’s t test for continuous variables, and the chi-square test
or Fisher’s exact test for categoric variables. The Kolmogorov-
Smirnov test was performed to determine the normality of the
distribution of parameters. If the resulting data did not show
a normal distribution, geometric mean ± SD was reported;
the Mann-Whitney U test or Kruskal-Wallis test was used for
multiple comparisons. Pearson’s correlation analysis and the
multivariable linear regression model was used to evaluate the
factors associated with vitamin D concentrations. Moreover,
general linear regression analysis was performed to assess
the relationship between eGFR and vitamin D concentrations.
Logistic regression analysis was used to evaluate the association
between RHF and serum 25(OH)D concentration. ORs for
RHF were compared among groups according to stratified
25(OH)D concentrations (<10, 10–20, 20–30, and ≥30 ng/mL).
Multivariable models were also constructed after adjustment
for confounding factors. Variables that showed statistical sig-
nificance (P < 0.05) in the univariable analysis were included
in the multivariable models. Variables that did not meet the
statistical criteria were included if they were considered to have
clinical significance. Restricted cubic splines were used as the
smoothing technique, and the spline degrees of freedom were
selected on the basis of the lowest set. For sensitivity analysis,
28,957 subjects with available information regarding vitamin
supplements were further analyzed. In those subgroups, vitamin
supplementation was added for adjustment factor in multivariate
logistic regression analysis. For all analyses, a P value <0.05 was
considered statistically significant.
RESULTS
Baseline characteristics
The baseline characteristics of the study subjects are shown in
Table 1. The mean age of study subjects was 48.1 ± 15.9 y and
18,779 (56.5%) subjects were female. In the group with 25(OH)D
<10 ng/mL, subjects tended to be younger and more often female
than in the other groups. BMI and SBP were lower in the group
with 25(OH)D <10 ng/mL. Histories of hypertension and activity
restriction were less prevalent in the group with 25(OH)D <10
ng/mL than in the ≥30 ng/mL group. The mean eGFR of total
subjects was 96.3 ± 15.5 mL · min–1 · 1.73 m–2 . The baseline
eGFR was 101.1 ± 16.5 mL · min–1 · 1.73 m–2 in the 25(OH)D
<10 ng/mL group and 90.8 ± 14.2 mL · min–1 · 1.73 m–2
in the ≥30 ng/mL group. The mean 25(OH)D concentration
in the study subjects was 17.9 ± 6.5 ng/mL. The amounts of
hemoglobin, fasting plasma glucose, total cholesterol, and ferritin
 VITAMIN D DEFICIENCY AND RENAL HYPERFILTRATION 1345
TABLE 1
Baseline characteristics in study subjects1

Vitamin D concentration

Total <10 ng/mL 10–19.9 ng/mL 20–29.9 ng/mL ≥30 ng/mL

(n = 33,210) (n = 2693) (n = 19,888) (n = 8858) (n = 1771)
Demographic data
Age, y 48.1 ± 15.9 43.8 ± 16.5 46.3 ± 15.7 52.0 ± 15.3 55.4 ± 14.4
Female, n (%) 18,779 (56.5) 1960 (72.8) 1,1918 (59.9) 4153 (46.9) 748 (42.2)
BMI, kg/m2 23.6 ± 3.3 23.0 ± 3.6 23.6 ± 3.4 23.8 ± 3.1 23.4 ± 3.1
SBP, mm Hg 118.3 ± 17.0 115.6 ± 17.6 117.4 ± 16.7 120.3 ± 17.1 121.6 ± 17.1
Activity restriction, n (%) 3962 (12.1) 318 (12.0) 2048 (10.5) 1276 (14.6) 320 (18.2)
Hypertension, n (%) 6090 (18.3) 381 (14.1) 3335 (16.8) 1926 (21.7) 448 (25.3)
Diabetes, n (%) 2178 (6.6) 172 (6.4) 1180 (5.9) 675 (7.6) 151 (8.5)
Proteinuria, n (%) 833 (2.5) 72 (2.7) 507 (2.5) 219 (2.5) 35 (2.0)

Downloaded from https://academic.oup.com/ajcn/article/108/6/1342/5239885 by guest on 28 October 2020

Stroke, n (%) 506 (1.5) 39 (1.5) 263 (1.3) 163 (1.9) 41 (2.3)
MI, n (%) 200 (0.6) 11 (0.4) 111 (0.6) 65 (0.7) 13 (0.7)
Laboratory data
eGFR, mL · min–1 · 1.73 m–2 96.3 ± 15.5 101.1 ± 16.5 97.7 ± 15.4 92.9 ± 14.5 90.8 ± 14.2
25(OH)D, ng/mL 17.9 ± 6.5 8.4 ± 1.4 15.1 ± 2.7 23.8 ± 2.7 34.1 ± 3.9
Hemoglobin, g/dL 14.0 ± 1.6 13.5 ± 1.7 13.9 ± 1.6 14.2 ± 1.5 14.2 ± 1.5
Ferritin, ng/mL 59.0 (29.0, 104.0) 39.0 (17.0, 76.5) 55.0 (27.0, 100.0) 69.0 (38.0, 116.0) 75.0 (43.0, 125.0)
FPG, mg/dL 97.3 ± 21.5 95.7 ± 21.9 96.9 ± 21.8 98.4 ± 21.0 98.9 ± 19.3
HbA1c, % 5.9 ± 0.9 5.8 ± 1.1 5.8 ± 0.9 6.0 ± 0.9 6.1 ± 0.9
Total cholesterol, mg/dL 188.2 ± 35.9 182.9 ± 35.9 187.9 ± 36.1 190.0 ± 35.2 189.0 ± 35.4
LDL cholesterol, mg/dL 113.8 ± 32.5 112.8 ± 34.0 113.6 ± 32.5 114.8 ± 32.3 112.8 ± 31.3
HDL cholesterol, mg/dL 49.4 ± 11.7 49.9 ± 11.7 49.7 ± 11.7 48.6 ± 11.4 48.5 ± 11.5
ALP, IU/L 224.4 ± 73.3 224.4 ± 82.5 222.2 ± 74.2 227.9 ± 70.7 228.1 ± 65.3
PTH,2 pg/mL 66.4 ± 27.1 82.8 ± 47.2 68.7 ± 26.4 62.3 ± 24.0 59.4 ± 21.1
1 Values are means ± SDs by ANOVA, or medians (IQRs) by Kruskal-Wallis test, unless otherwise indicated. ALP, alkaline phosphatase; eGFR,

estimated glomerular filtration rate; FPG, fasting plasma glucose; HbA1c, glycated hemoglobin; MI, myocardial infarction; PTH, parathyroid hormone; SBP,
systolic blood pressure; 25(OH)D, 25-hydroxyvitamin D.
2 PTH was measured in 10,136 participants. The values for the groups with <10, 10–19.9, 20–29.9, and ≥30 ng/mL were 508, 5161, 3532, and 935,

respectively.

were lower, whereas PTH concentrations were higher, in the
25(OH)D <10 ng/mL group than in the ≥30 ng/mL group. PTH
was only measured in 10,136 participants and its mean value for
all subjects was 66.4 ± 27.1 pg/mL.
Association of adjusted mean of eGFR and serum vitamin D
concentrations
Pearson’s correlation analysis indicated that vitamin D con-
centrations were negatively associated with eGFR (r = −0.19,
P < 0.001). In a multivariable linear regression model, vitamin
D concentrations were related to clinical factors: they were
negatively associated with eGFR (β = −0.02; 95% CI: −0.02,
−0.01; P < 0.001), as well as BMI, SBP, and fasting plasma
glucose, whereas they were positively associated with age and
hemoglobin (Supplemental Table 1). Next, we examined the
association between adjusted mean eGFR and serum vitamin
D concentrations treated as linear covariate. The adjusted mean
eGFR significantly increased with decreasing amounts of vitamin
D after adjustment for age, sex, and history of hypertension
or diabetes (Figure 2A). A general linear regression model
was used to further assess the relationship between eGFR and
vitamin D status groups, adjusting for age, sex, BMI, history
of hypertension or diabetes, hemoglobin, and LDL cholesterol.
When the subjects were categorized into 4 groups according
to vitamin D concentration, the adjusted mean eGFR was
significantly higher in the group with 25(OH)D <10 ng/mL than
in the other groups [adjusted mean eGFR = 100.2 mL · min–1 ·
1.73 m–2 (95% CI: 99.3, 101.1 mL · min–1 · 1.73 m–2 ), 98.6 mL ·
min–1 · 1.73 m–2 (95% CI: 98.3, 98.9 mL · min–1 · 1.73 m–2 ), 97.4
mL · min–1 · 1.73 m–2 (95% CI: 96.9, 97.8 mL · min–1 · 1.73 m–2 ),
and 98.1 mL · min–1 · 1.73 m–2 (95% CI: 96.8, 99.3 mL · min–1
· 1.73 m–2 ) in the groups with 25(OH)D concentrations of <10,
10–19.9, 20–29.9, and ≥30 ng/mL, respectively, P-trend < 0.001;
Figure 2B].
Prevalence of RHF according to vitamin D status
Because the adjusted mean eGFR was higher in the vitamin
D–deficient groups, the prevalence of RHF according to vitamin
D concentration was assessed. RHF was defined as a logarithm-
transformed eGFR with an adjusted residual >95th percentile.
The results showed that the prevalence of RHF was significantly
higher in the 25(OH)D <10 ng/mL group than in the others
(5.8%, 4.6%, 4.4%, and 5.0% in the groups with 25(OH)D
<10, 10–19.9, 20–29.9, and ≥30 ng/mL, respectively; Figure 3).
Furthermore, we evaluated baseline differences among the
25(OH)D <10 ng/mL group with or without RFH (n = 2693).
The subjects with RHF showed significantly higher proportions
of men and history of hypertension, diabetes, and stroke,
and higher BMIs and SBP than did those without RHF. The
subjects with RHF also showed significantly higher amounts of
eGFR, fasting plasma glucose, glycated hemoglobin, and alkaline
phosphates than did those without RHF (Supplemental Table 2).
1346 JHEE ET AL.
FIGURE 2 Association of eGFR and vitamin D concentrations (A). The
adjusted mean eGFR was calculated using a multivariable linear model, after
adjustment for confounding variables (see Methods for details), and vitamin D
concentrations were treated as a linear variable (n = 33,210). (B) The adjusted
mean eGFR stratified according to vitamin D concentration using a general
linear model after adjustment for possible confounding factors. The error bars
represent 95% CIs of the adjusted mean, and asterisks indicate significant
differences from the group with vitamin D sufficiency (P-trend <0.001).
eGFR, estimated glomerular filtration rate; 25(OH)D, 25-hydroxyvitamin D.
The association between RHF and serum vitamin D
concentrations
To test whether vitamin D deficiency is related to an increased
risk of RHF, we performed multivariable logistic regression
analysis treating vitamin D concentrations as a linear variable.
The crude model showed that the OR for RHF increased as
Downloaded from https://academic.oup.com/ajcn/article/108/6/1342/5239885 by guest on 28 October 2020
FIGURE 3 The prevalence of RHF according to groups with differ-
ent vitamin D concentrations. RHF, renal hyperfiltration; 25(OH)D, 25-
hydroxyvitamin D.
serum vitamin D concentration decreased (OR: 1.18; 95% CI:
1.17, 1.19). This association was still significant even after
full adjustment for confounding factors (OR: 1.02; 95%, CI:
1.01, 1.04) (Table 2). Restricted cubic splines showed that the
ORs increased with decreasing vitamin D concentration, starting
from <10 ng/dL (Figure 4).The relationship between RHF and
vitamin D categorized according to serum concentrations was
assessed using logistic regression analysis. First, unadjusted
analysis was performed and the results showed that groups with
25(OH)D concentrations of 20–29.9, 10–19.9, and <10 ng/mL
were at higher risk of RHF than the group with ≥30 ng/mL;
after adjustment for age and sex, the 25(OH)D <10 ng/mL group
showed the highest risk of RHF (Supplemental Table 3). Finally,
the ORs for RHF were significantly higher in the 25(OH)D
<10 ng/mL group than in the ≥30 ng/mL group even after
adjustment for age, sex, BMI, history of hypertension or diabetes,
hemoglobin, and LDL choleseterol. Figure 5 shows the fully
adjusted ORs of RHF for each group [fully adjusted OR in
the 25(OH)D <10 ng/mL group, 2.41 (95% CI: 1.72, 3.43);
in the 10–19.9 ng/mL group, 1.15 (95% CI: 0.87, 1.43); in
the 20–29.9 ng/mL group, 1.53 (95% CI: 0.91, 2.47); the ≥30
ng/mL group was treated as the reference]. Because nutritional
food intake may influence serum vitamin D concentrations as
well as RHF, we further adjusted for dietary factors including
daily amount of total calorie and protein intake in multivariable
regression analysis. After adjustment, the 25(OH)D <10 ng/mL
group was still independently associated with increased ORs for
RHF (Supplemental Figure 1).
Subgroup analysis
Clinical factors such as age, gender, history of diabetes
and hypertension, and obesity can interact with the association
between RHF and serum vitamin D status. Thus, we performed
subgroup analysis stratified by age, gender, history of diabetes
 VITAMIN D DEFICIENCY AND RENAL HYPERFILTRATION 1347
TABLE 2
Logistic regression analysis for RHF according to serum vitamin D concentrations1

Crude2 Model 13 Model 24

OR (95% CI) P OR (95% CI) P OR (95% CI) P

Vitamin D (per 1-ng/mL decrease) 1.18 (1.17, 1.19) <0.001 1.03 (1.02, 1.04) <0.001 1.02 (1.01, 1.04) 0.02
Age (per 1-y increase) — 0.99 (0.98, 0.99) <0.001 0.99 (0.98, 1.00) 0.15
Sex (female vs. male) — 0.25 (0.23, 0.28) <0.001 0.27 (0.20, 0.36) <0.001
BMI (per 1-kg/m2 increase) — — 1.06 (1.03, 1.09) <0.001
Hypertension (yes vs. no) — — 1.62 (1.24, 2.11) <0.001
Diabetes (yes vs. no) — — 1.84 (1.33, 2.54) <0.001
Hemoglobin (per 1-g/dL increase) — — 0.84 (0.77, 0.91) <0.001
LDL cholesterol (per 1-mg/dL increase) — — 0.99 (0.99, 1.00) 0.08
1 All
values are ORs (95% CIs). RHF, renal hyperfiltration.

Downloaded from https://academic.oup.com/ajcn/article/108/6/1342/5239885 by guest on 28 October 2020

2 Crude:unadjusted model.
3 Model 1: adjusted for age and sex.
4 Model 2: adjusted for model 1 + BMI, hypertension, diabetes, hemoglobin, and LDL cholesterol.

and hypertension, and obesity. We defined obesity as BMI
(in kg/m2 ) ≥25 according to WHO recommendations for
Asian populations (32). Increased ORs of RHF associated with
25(OH)D concentrations <10 ng/mL were consistent in sub-
groups with young ages, no diabetes, and nonobese, but showed
no association with gender and hypertension; no significant
interactions were found across all subgroups (Figure 6).
Sensitivity analysis
The impact of vitamin D deficiency on RHF was further
evaluated in the subgroup that included subjects taking vitamin
supplements (n = 28,957). First, the prevalence of RHF among
groups stratified according to vitamin D serum concentrations
was assessed and the results consistently showed that the
25(OH)D <10 ng/mL group had the highest prevalence of RHF
[6.0%, 5.7%, 5.2%, and 4.5% in the 25(OH)D <10, 10–19.9,
20–29.9, and ≥30 ng/mL groups, respectively; Supplemental
Figure 2]. Next, the ORs of RHF were evaluated across
each group. The highest risk of RHF in the 25(OH)D <10
ng/mL group remained a consistent event after adjustment
for vitamin supplementation (OR: 2.28; 95% CI: 1.63, 3.18;
P < 0.001; Supplemental Figure 3). Furthermore, we performed
propensity score matching (PSM) analysis. In PSM, subjects
were classified into 2 groups with or without vitamin D
supplements. Subsequently, we determined the propensity score
using binary logistic regression with greedy nearest-neighbor
matching technique without replacement. We used a caliper of
0.2 times the SD. Covariates for PSM were age, sex, BMI,
SBP, histories of hypertension or diabetes, LDL cholesterol, and
hemoglobin. PSM yielded 10,424 matched pairs (1:1 ratio) of

FIGURE 4 Association of serum vitamin D concentrations with ORs FIGURE 5 Adjusted ORs of RHF according to groups with different
for RHF in fully adjusted logistic regression model using restricted cubic vitamin D concentrations. Black squares indicate ORs, and the error bars
splines. Black line shows ORs, and dotted lines represent 95% CIs. RHF, represent 95% CIs. ∗ P < 0.001 compared with reference group. RHF, renal
renal hyperfiltration; 25(OH)D, 25-hydroxyvitamin D. hyperfiltration; 25(OH)D, 25-hydroxyvitamin D.
1348 JHEE ET AL.

Downloaded from https://academic.oup.com/ajcn/article/108/6/1342/5239885 by guest on 28 October 2020

FIGURE 6 Forest plots for the subgroup analyses of RHF according to groups with different vitamin D concentrations. All models were adjusted for age,
sex, BMI, history of hypertension or diabetes, hemoglobin, and LDL cholesterol. RHF, renal hyperfiltration.

the subjects. The 2 groups were well matched for all baseline
characteristics. In the matched cohort, the association between
vitamin D status and RHF was analyzed with logistic regression
analysis. The results were equal to those before PSM, as
25(OH)D <10 ng/mL still significantly increased the ORs for
RHF (Supplemental Table 4).
DISCUSSION
This study observed a significant association between rates
of RHF and severe vitamin D deficiency adjusted for age,
sex, height, weight, and history of hypertension or diabetes in
healthy adults from a large Korean community-based cohort.
We demonstrated that the adjusted mean eGFR was negatively
associated with serum vitamin D concentrations, and the
prevalence of RHF was higher in subjects with 25(OH)D <10
ng/mL. Finally, the relative risk of RHF was significantly higher
in subjects with 25(OH)D <10 ng/mL than in those with ≥30
ng/mL. These findings suggest that 25(OH)D <10 ng/mL is a
robust risk factor for RHF in a relatively healthy population.
RHF is likely to play a crucial role in the development and
progression of CKD (1). In the early 1980s Brenner et al.
(33) proposed the “hyperfiltration theory,” in which progressive
deterioration of kidney function was a result of compensatory
 VITAMIN D DEFICIENCY AND RENAL HYPERFILTRATION
glomerular hemodynamic changes occurring in response to
nephron loss. Currently, various conditions have been suggested
to be associated with RHF, including pregnancy, high-protein
diets, early phases of diabetes, autosomal dominant polycystic
kidney disease, and obesity (34–37). The possible mechanisms
for glomerular hyperfiltration include an increased filtration
fraction, which in turn decreases the effective renal plasma flow
more than the GFR; vasodilatation of the afferent arteriole; and
activation of the renin-angiotensin-aldosterone system (RAAS)
(38, 39). Glomerular hyperfiltration and increased glomerular
pressure causing glomerular hypertension lead to progressive
kidney disease as occurs in patients with diabetes, autosomal
dominant polycystic kidney disease, and obesity (1). Previous
epidemiologic studies have also demonstrated several factors
instigating RHF, not only in CKD, but also in a healthy cohort.
Glomerular hyperfiltration is observed in the early course of
diabetes, and is considered to be a risk factor for progression
of diabetic nephropathy (2, 29). The early stage of hypertension
is also associated with an increased prevalence of glomerular
hyperfiltration due to an elevated glomerular hydraulic pressure
(9). Furthermore, several study groups have reported that de-
creased physical activity is associated with increased glomerular
hyperfiltration in the general population (29, 40).
Vitamin D plays an essential role in the control of bone
metabolism (41). However, growing evidence suggests that the
vitamin D receptor is expressed in most tissues and cells, and has
pleiotropic effects (11). One of these is the renoprotective effect
interacting with suppression of the RAAS (41). To date, 2 major
study groups have demonstrated that active vitamin D binds to the
promoter region of the renin gene to downregulate the expression
of renal renin mRNA (42, 43). Mizobuchi et al. (44) identified
experimentally that the addition of vitamin D to RAAS blockade
therapy improved the efficacy of RAAS treatment by blunting the
reactive rise in renin. Previously, a randomized controlled trial
demonstrated that the addition of selective vitamin D receptor
activator to RAAS inhibition lowered albuminuria in patients
with diabetic nephropathy (23). Moreover, an improvement in
proteinuria has been reported after adding active vitamin D to
RAAS blockers in patients with IgA nephropathy (22). Based on
these observations, it is possible that the state of severe vitamin
D deficiency might have reduced the effects on the suppression
of activated RAAS, which results in glomerular hyperfiltration.
It is well known that vitamin D deficiency is a more prevalent
and severe issue in patients with CKD, and in particular in
those on dialysis, than in the general population (45, 46).
Both experimental and clinical studies have demonstrated that
25(OH)D is a suppressor of renin biosynthesis, and that vitamin
D deficiency can be the risk factor for CKD progression (47).
Moreover, several studies have argued that vitamin D deficiency
is a significant predictor for mortality in subjects with CKD
(19). However, growing evidence suggests that in the general
population, vitamin D deficiency is independently associated
with an increased risk of adverse clinical outcomes (48, 49).
Our findings are in accordance with these previous reports in
which severe vitamin D deficiency is associated with RHF, which
is a potential risk factor for deteriorating kidney function in
relatively healthy adults. Furthermore, the prevalence of vitamin
D deficiency is reported to be especially high in South Korea
(50, 51). In fact, our study data showed a higher prevalence of
vitamin D deficiency, ≤68%, than those of Caucasians reported
1349
in the NHANES study (52). Although little is known about
the exact contributors to the high prevalence of vitamin D
deficiency among Korean adults, several plausible explanations
have been suggested. Adults of Korean descent are more
likely to be dark-skinned than those of Caucasian descent, and
basal darker-colored skin can reduce the ultraviolet radiation–
mediated synthesis of vitamin D upon the same dose of sun
exposure. Second, vitamin D–fortified foods as well as vitamin D
supplements are less readily available in Korea than in Western
countries. Third, cultural habits, such as avoiding direct sun
exposure and wearing more clothing, result in absorption of
lower amounts of ultraviolet radiation. All together, it cannot
be emphasized enough that early screening and management of
vitamin D deficiency is beneficial to maintaining normal renal
Downloaded from https://academic.oup.com/ajcn/article/108/6/1342/5239885 by guest on 28 October 2020
function in the general population.
This study has several limitations. First, GFR was not
directly measured by the gold standard method using inulin
or radioisotopes. GFR was estimated from the Chronic Kidney
Disease Epidemiology Collaboration equation, and statistical
assessments were used to define RHF. It is difficult to establish a
clear definition of RHF due to several factors: the large variety of
methods used to measure GFR, the natural decline in GFR with
aging, and the differences between sexes and distinct ethnicities
(53). Therefore, in this study, we defined RHF after adjustment
for age, sex, height, weight, and history of hypertension or
diabetes, which is a widely accepted method used in several
past studies (4, 29, 54). Second, the definition of RHF did not
determine whether it occurred in a single nephron or throughout
the whole kidney. The mechanisms of glomerular hyperfiltration
at the single-nephron and whole-kidney level may differ (55).
Nevertheless, the design of this study was based on pre-existing
clinical data and was not experimental, thus single-nephron
RHF could not have been measured. Third, medication records
describing details of vitamin D supplementation were lacking in
our data. Administration of vitamin D as supplements may affect
serum vitamin D concentrations as well as renal function (22,
23, 44, 56). Therefore, this study is limited in its analyses of
the effects of vitamin D supplementation not only on vitamin D
serum concentrations, but also on renal function. However, for
this reason, we performed sensitivity analysis in a group of
28,957 subjects who had used vitamin supplements. Finally,
by virtue of its cross-sectional observational study design,
the present study does not include any information regarding
longitudinal data or interventions. Thus, our data are limited
to proving causality between RHF and vitamin D deficiency,
and to support the benefit of therapeutic supplementation with
vitamin D in subjects with normal renal function. Further
longitudinal studies are warranted and interventional studies
with vitamin D supplementation may represent a worthwhile
approach.
In conclusion, this study is the first to demonstrate severe
vitamin D deficiency as a candidate risk factor for RHF in
relatively healthy adults using data from a large nationwide
community–based cohort. This association might be due to
the elimination of the effects of vitamin D, which suppresses
RAAS and leads to reduced glomerular hypertension and
hyperfiltration. These findings suggest that early screening
and management of severe vitamin D deficiency is bene-
ficial for protecting renal function in a relatively healthy
population.
1350 JHEE ET AL.
The authors’ contributions were as follows—JHJ and THY: conceived
of the research idea and designed the study; JHJ: acquired the data; KHN,
SYA, MUC, ML, SP, HK, and HRY: analyzed and interpreted the data;
JHJ and YKK: performed the statistical analysis; JTP, SHH, SWK, and
THY: supervised or mentored; THY: held responsibility to ensure that this
study was reported honestly, accurately, and transparently, that no important
aspects of the study have been omitted, and that any discrepancies from
the study as planned have been explained; and all authors: contributed
important intellectual content during manuscript drafting or revision and
are accountable 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, and read and approved the final manuscript. The
authors reported no funding received for this study. All authors declare no
conflicts of interests.
REFERENCES
1. Helal I, Fick-Brosnahan GM, Reed-Gitomer B, Schrier RW. Glomerular
hyperfiltration: definitions, mechanisms and clinical implications. Nat
Rev Nephrol 2012;8:293–300.
2. Ruggenenti P, Porrini EL, Gaspari F, Motterlini N, Cannata A, Carrara
F, Cella C, Ferrari S, Stucchi N, Parvanova A, et al. Glomerular
hyperfiltration and renal disease progression in type 2 diabetes. Diabetes
Care 2012;35:2061–8.
3. Palatini P, Mormino P, Dorigatti F, Santonastaso M, Mos L, De Toni
R, Winnicki M, Dal Follo M, Biasion T, Garavelli G, et al. Glomerular
hyperfiltration predicts the development of microalbuminuria in stage 1
hypertension: the HARVEST. Kidney Int 2006;70:578–84.
4. Park M, Yoon E, Lim YH, Kim H, Choi J, Yoon HJ. Renal
hyperfiltration as a novel marker of all-cause mortality. J Am Soc
Nephrol 2015;26:1426–33.
5. Cherney DZI, Zinman B, Inzucchi SE, Koitka-Weber A, Mattheus
M, von Eynatten M, Wanner C. Effects of empagliflozin on the
urinary albumin-to-creatinine ratio in patients with type 2 diabetes and
established cardiovascular disease: an exploratory analysis from the
EMPA-REG OUTCOME randomised, placebo-controlled trial. Lancet
Diabetes Endocrinol 2017;5:610–21.
6. Nelson RG, Bennett PH, Beck GJ, Tan M, Knowler WC, Mitch
WE, Hirschman GH, Myers BD. Development and progression of
renal disease in Pima Indians with non-insulin-dependent diabetes
mellitus. Diabetic Renal Disease Study Group. N Engl J Med 1996;335:
1636–42.
7. Schmieder RE, Messerli FH, Garavaglia G, Nunez B. Glomerular
hyperfiltration indicates early target organ damage in essential
hypertension. Jama 1990;264:2775–80
8. Chagnac A, Weinstein T, Herman M, Hirsh J, Gafter U, Ori Y. The
effects of weight loss on renal function in patients with severe obesity.
J Am Soc Nephrol 2003;14:1480–6
9. Okada R, Yasuda Y, Tsushita K, Wakai K, Hamajima N, Matsuo S.
Glomerular hyperfiltration in prediabetes and prehypertension. Nephrol
Dial Transplant 2012;27:1821–5.
10. Maeda I, Hayashi T, Sato KK, Koh H, Harita N, Nakamura Y, Endo
G, Kambe H, Fukuda K. Cigarette smoking and the association with
glomerular hyperfiltration and proteinuria in healthy middle-aged men.
Clin J Am Soc Nephrol 2011;6:2462–9.
11. Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266–81.
12. Bischoff-Ferrari HA, Willett WC, Orav EJ, Lips P, Meunier PJ, Lyons
RA, Flicker L, Wark J, Jackson RD, Cauley JA, et al. A pooled analysis
of vitamin D dose requirements for fracture prevention. N Engl J Med
2012;367:40–9.
13. Choi HM, Hyun YY, Lee KB, Kim H. High estimated glomerular
filtration rate is associated with coronary artery calcification in middle-
aged Korean men without chronic kidney disease. Nephrol Dial
Transplant 2015;30:996–1001.
14. DeLuca HF. Overview of general physiologic features and functions of
vitamin D. Am J Clin Nutr 2004;80:1689s–96s.
15. Dusso AS, Brown AJ, Slatopolsky E. Vitamin D. Am J Physiol Renal
Physiol 2005;289:F8–28.
16. Giovannucci E, Liu Y, Rimm EB, Hollis BW, Fuchs CS, Stampfer MJ,
Willett WC. Prospective study of predictors of vitamin D status and
cancer incidence and mortality in men. J Natl Cancer Inst 2006;98:
451–9.
17. Cantorna MT, Zhu Y, Froicu M, Wittke A. Vitamin D status, 1,25-
dihydroxyvitamin D3, and the immune system. Am J Clin Nutr
2004;80:1717s–20s.
18. Zittermann A, Schleithoff SS, Tenderich G, Berthold HK, Korfer
R, Stehle P. Low vitamin D status: a contributing factor in the
pathogenesis of congestive heart failure? J Am Coll Cardiol 2003;41:
105–12
19. Pilz S, Iodice S, Zittermann A, Grant WB, Gandini S. Vitamin D status
and mortality risk in CKD: a meta-analysis of prospective studies. Am
J Kidney Dis 2011;58:374–82.
20. Urena-Torres P, Metzger M, Haymann JP, Karras A, Boffa JJ, Flamant
M, Vrtovsnik F, Gauci C, Froissart M, Houillier P, et al. Association
of kidney function, vitamin D deficiency, and circulating markers
of mineral and bone disorders in CKD. Am J Kidney Dis 2011;58:
544–53.
21. Uhlig K, Berns JS, Kestenbaum B, Kumar R, Leonard MB, Martin
KJ, Sprague SM, Goldfarb S. KDOQI US commentary on the 2009
Downloaded from https://academic.oup.com/ajcn/article/108/6/1342/5239885 by guest on 28 October 2020
KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, and
Treatment of CKD-Mineral and Bone Disorder (CKD-MBD). Am J
Kidney Dis 2010;55:773–99.
22. Liu LJ, Lv JC, Shi SF, Chen YQ, Zhang H, Wang HY. Oral calcitriol for
reduction of proteinuria in patients with IgA nephropathy: a randomized
controlled trial. Am J Kidney Dis 2012;59:67–74.
23. de Zeeuw D, Agarwal R, Amdahl M, Audhya P, Coyne D, Garimella
T, Parving HH, Pritchett Y, Remuzzi G, Ritz E, et al. Selective vitamin
D receptor activation with paricalcitol for reduction of albuminuria in
patients with type 2 diabetes (VITAL study): a randomised controlled
trial. Lancet 2010;376:1543–51.
24. Zhang Y, Kong J, Deb DK, Chang A, Li YC. Vitamin D receptor
attenuates renal fibrosis by suppressing the renin-angiotensin system.
J Am Soc Nephrol 2010;21:966–73.
25. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley
DA, Heaney RP, Murad MH, Weaver CM. Evaluation, treatment,
and prevention of vitamin D deficiency: an Endocrine Society
clinical practice guideline. J Clin Endocrinol Metab 2011;96:
1911–30.
26. Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK,
Durazo-Arvizu RA, Gallagher JC, Gallo RL, Jones G, et al. The 2011
report on dietary reference intakes for calcium and vitamin D from the
Institute of Medicine: what clinicians need to know. J Clin Endocrinol
Metab 2011;96:53–8.
27. Selvin E, Manzi J, Stevens LA, Van Lente F, Lacher DA, Levey AS,
Coresh J. Calibration of serum creatinine in the National Health and
Nutrition Examination Surveys (NHANES) 1988–1994, 1999–2004.
Am J Kidney Dis 2007;50:918–26.
28. Earley A, Miskulin D, Lamb EJ, Levey AS, Uhlig K. Estimating
equations for glomerular filtration rate in the era of creatinine
standardization: a systematic review. Ann Intern Med 2012;156:785–
95.
29. Melsom T, Mathisen UD, Ingebretsen OC, Jenssen TG, Njolstad I,
Solbu MD, Toft I, Eriksen BO. Impaired fasting glucose is associated
with renal hyperfiltration in the general population. Diabetes Care
2011;34:1546–51.
30. Inker LA, Schmid CH, Tighiouart H, Eckfeldt JH, Feldman HI, Greene
T, Kusek JW, Manzi J, Van Lente F, Zhang YL, et al. Estimating
glomerular filtration rate from serum creatinine and cystatin C. N Engl
J Med 2012;367:20–9.
31. Jeong TD, Lee W, Yun YM, Chun S, Song J, Min WK. Development
and validation of the Korean version of CKD-EPI equation to estimate
glomerular filtration rate. Clin Biochem 2016;49:713–9.
32. WHO Expert Consultation. Appropriate body-mass index for Asian
populations and its implications for policy and intervention strategies.
Lancet 2004;363:157–63.
33. Brenner BM, Hostetter TH, Olson JL, Rennke HG, Venkatachalam MA.
The role of glomerular hyperfiltration in the initiation and progression
of diabetic nephropathy. Acta Endocrinol Suppl (Copenh) 1981;242:
7–10
34. Bergstrom J, Ahlberg M, Alvestrand A. Influence of protein intake on
renal hemodynamics and plasma hormone concentrations in normal
subjects. Acta Med Scand 1985;217:189–96
35. Bank N. Mechanisms of diabetic hyperfiltration. Kidney Int
1991;40:792–807
36. Wong H, Vivian L, Weiler G, Filler G. Patients with autosomal dominant
polycystic kidney disease hyperfiltrate early in their disease. Am J
Kidney Dis 2004;43:624–8
 VITAMIN D DEFICIENCY AND RENAL HYPERFILTRATION
37. Wuerzner G, Pruijm M, Maillard M, Bovet P, Renaud C, Burnier
M, Bochud M. Marked association between obesity and glomerular
hyperfiltration: a cross-sectional study in an African population. Am
J Kidney Dis 2010;56:303–12.
38. Huang SH, Sharma AP, Yasin A, Lindsay RM, Clark WF, Filler G.
Hyperfiltration affects accuracy of creatinine eGFR measurement. Clin
J Am Soc Nephrol 2011;6:274–80.
39. Schrier RW. Systemic arterial vasodilation, vasopressin, and
vasopressinase in pregnancy. J Am Soc Nephrol 2010;21:
570–2.
40. Melsom T, Mathisen UD, Eilertsen BA, Ingebretsen OC, Jenssen T,
Njolstad I, Solbu MD, Toft I, Eriksen BO. Physical exercise, fasting
glucose, and renal hyperfiltration in the general population: the Renal
Iohexol Clearance Survey in Tromso 6 (RENIS-T6). Clin J Am Soc
Nephrol 2012;7:1801–10.
41. Doorenbos CR, van den Born J, Navis G, de Borst MH. Possible
renoprotection by vitamin D in chronic renal disease: beyond mineral
metabolism. Nat Rev Nephrol 2009;5:691–700.
42. Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP. 1,25-
Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-
angiotensin system. J Clin Invest 2002;110:229–38.
43. van Paassen P, de Zeeuw D, Navis G, de Jong PE. Renal and
systemic effects of continued treatment with renin inhibitor remikiren in
hypertensive patients with normal and impaired renal function. Nephrol
Dial Transplant 2000;15:637–43
44. Mizobuchi M, Morrissey J, Finch JL, Martin DR, Liapis H, Akizawa
T, Slatopolsky E. Combination therapy with an angiotensin-converting
enzyme inhibitor and a vitamin D analog suppresses the progression of
renal insufficiency in uremic rats. J Am Soc Nephrol 2007;18:1796–
806.
45. LaClair RE, Hellman RN, Karp SL, Kraus M, Ofner S, Li Q, Graves
KL, Moe SM. Prevalence of calcidiol deficiency in CKD: a cross-
sectional study across latitudes in the United States. Am J Kidney Dis
2005;45:1026–33
46. Del Valle E, Negri AL, Aguirre C, Fradinger E, Zanchetta JR.
Prevalence of 25(OH) vitamin D insufficiency and deficiency in
1351
chronic kidney disease stage 5 patients on hemodialysis. Hemodial Int
2007;11:315–21.
47. Fernandez-Juarez G, Luno J, Barrio V, de Vinuesa SG, Praga M,
Goicoechea M, Lahera V, Casas L, Oliva J. 25 (OH) vitamin D
levels and renal disease progression in patients with type 2 diabetic
nephropathy and blockade of the renin-angiotensin system. Clin J Am
Soc Nephrol 2013;8:1870–6.
48. Autier P, Gandini S. Vitamin D supplementation and total mortality:
a meta-analysis of randomized controlled trials. Arch Intern Med
2007;167:1730–7.
49. Melamed ML, Michos ED, Post W, Astor B. 25-Hydroxyvitamin D
levels and the risk of mortality in the general population. Arch Intern
Med 2008;168:1629–37.
50. Satirapoj B, Limwannata P, Chaiprasert A, Supasyndh O, Choovichian
P. Vitamin D insufficiency and deficiency with stages of chronic kidney
disease in an Asian population. BMC Nephrol 2013;14:206.
51. Choi EY. 25(OH)D status and demographic and lifestyle determinants
Downloaded from https://academic.oup.com/ajcn/article/108/6/1342/5239885 by guest on 28 October 2020
of 25(OH)D among Korean adults. Asia Pac J Clin Nutr 2012;21:
526–35
52. Liu X, Baylin A, Levy PD. Vitamin D deficiency and insufficiency
among US adults: prevalence, predictors and clinical implications. Br J
Nutr 2018;119:928–36.
53. Cachat F, Combescure C, Cauderay M, Girardin E, Chehade
H. A systematic review of glomerular hyperfiltration assessment
and definition in the medical literature. Clin J Am Soc Nephrol
2015;10:382–9.
54. Oh SW, Han KH, Han SY. Associations between renal hyperfiltration
and serum alkaline phosphatase. PLoS One 2015;10:e0122921.
55. Hostetter TH, Olson JL, Rennke HG, Venkatachalam MA, Brenner BM.
Hyperfiltration in remnant nephrons: a potentially adverse response to
renal ablation. J Am Soc Nephrol 2001;12:1315–25
56. Lauretani F, Frondini C, Davoli ML, Martini E, Pellicciotti F, Zagatti
A, Giordano A, Zurlo A, Pioli G. Vitamin D supplementation is
required to normalize serum level of 25OH-vitamin D in older adults: an
observational study of 974 hip fracture inpatients. J Endocrinol Invest
2012;35:921–4.