J Nutr Sci Vitaminol, 64, 18–25, 2018

Parathyroid Hormone Levels Are Independently Associated

with eGFR and Albuminuria: The Dong-gu Study

Seong-Woo Choi1, Sun-Seog Kweon2,3, Young-Hoon Lee4, So-Yeon Ryu1, Jin-Su Choi2,
Hae-Sung Nam5, Kyeong-Soo Park6, Sun A Kim2 and Min-Ho Shin2,7,*
1 
Department of Preventive Medicine, Chosun University Medical School,
309, Pilmun-daero, Dong-gu, Gwangju 61452, Republic of Korea
2 
Department of Preventive Medicine, Chonnam National University Medical School,
264, Seoyang-ro, Hwasun 58128, Republic of Korea
3 
Jeonnam Regional Cancer Center, Chonnam National University Hwasun Hospital,
264, Seoyang-ro, Hwasun 58128, Republic of Korea
4 
Department of Preventive Medicine & Institute of Wonkwang Medical Science, Wonkwang
University School of Medicine, 460, Iksandae-ro, Iksan 54538, Republic of Korea
5 
Department of Preventive Medicine, Chungnam National University Medical School,
266, Munhwa-ro, Jung-gu, Daejeon 35015, Republic of Korea
6 
Department of Preventive Medicine, Seonam University College of Medicine,
439, Chunhyang-ro, Namwon 55724, Republic of Korea
7 
Center for Creative Biomedical Scientists, Chonnam National University,
77 Yongbong-ro, Buk-gu, Gwangju 61186, Republic of Korea
(Received July 3, 2017)

Summary  Increased parathyroid hormone (PTH) was associated with cardiovascular

mortality and morbidity in CKD patients. Our aim was to investigate the associations among
estimated glomerular filtration rate (eGFR), albumin/creatinine ratio (ACR) and PTH inde-
pendent of 25-hydroxyvitamin D (25(OH)D). This study included 9,162 individuals who
completed the baseline survey of the Dong-gu Study, which was conducted in Korea from
2007 to 2010. The eGFR, ACR, PTH and 25(OH)D were measured in participants who met
the detailed inclusion criteria. After being adjusting for covariates (sex, age, waist circumfer-
ence, smoking, alcohol intake, physical activity, hypertension medications, diabetes medica-
tion, total cholesterol, triglyceride, HDL cholesterol) and log-ACR, the PTH value stratified by
25(OH)D level significantly decreased with increasing eGFR levels in each 25(OH)D stratum.
Moreover, after adjustment for the same covariates and log-eGFR, the PTH value stratified
by 25(OH)D level significantly increased with increasing ACR levels in each 25(OH)D stra-
tum. In conclusion, the PTH values significantly decreased with increasing eGFR levels and
increased with increasing ACR levels independently of 25(OH)D in an adult Korean popula-
tion $50 y of age.
Key Words  parathyroid hormone, glomerular filtration rate, albuminuria, vitamin D

Chronic kidney disease (CKD), which is character-
ized by a low glomerular filtration rate (GFR), affects
10–15% of American adults (1). Impaired GFR is a risk
factor for cardiovascular disease (CVD) (2) and is cor-
related with cardiovascular mortality and morbidity in
high-risk groups (3, 4) and in the general population
(5). Albuminuria is a well-known predictor of CKD pro-
gression, end stage renal disease, cardiovascular events,
and mortality (6–8). Thus, the detection and treat-
ment of the risk factors associated with decreased GFR
and albuminuria will help prevent the progression of
advanced kidney disease and reduce the risk of cardio-
vascular events (9, 10).
Parathyroid hormone (PTH) is important for calcium
and phosphate homeostasis (11). Recently, it was shown
that increased PTH was associated with hypertension
* To whom correspondence should be addressed.
E-mail: mhshinx@paran.com
(12), insulin resistance (13), CVD, and increased mor-
tality in CKD patients (14). Thus, the National Kidney
Foundation’s Kidney Disease Outcomes Quality Initia-
tive (KDOQI) clinical practice guidelines recommend
the measurement of PTH concentrations in the early
course of CKD (GFR ,60 mL/min per 1.73 m2) (15).
In CKD patients, levels of plasma phosphate increase
while levels of plasma calcium and 1,25-dihydroxyvita-
min D (1,25(OH)2D) decrease; these changes result in
the development of hypocalcemia, which stimulates the
production of PTH (16). However, it is unclear whether
the relationship between kidney function and PTH
would remain, independent of vitamin D, in subjects
with a normal range of kidney function.
Although there is particular interest in the Korean
population, the population with the highest overall prev-
alence of vitamin D deficiency in the world (17), there is
a relative lack of studies investigating PTH in Koreans.
Furthermore, the burden of CKD is increasing in Korea.

18
 Parathyroid Hormone Levels Associated with eGFR and Albuminuria 19

Table  1.  Characteristics of the subjects according to eGFR levels.

eGFR (mL/min per 1.73 m2)

Variable Total p value
,30 30–44 45–59 60–89 $90

N (%) 59 (0.6) 300 (3.3) 1,815 (19.9) 6,354 (69.6) 604 (6.6) 9,132 (100.0)
Male (%) 28 (47.5) 142 (47.3) 809 (44.6) 2,493 (39.2) 181 (30.0) 3,653 (40.0) ,0.001
Age (y) 72.668.0 73.667.3 69.367.8 64.167.7 58.964.8 65.168.2 ,0.001
Height (cm) 159.169.2 157.469.4 158.668.7 158.368.3 157.467.7 158.368.4 0.013
Weight (kg) 62.0610.9 61.3610.3 61.969.3 60.969.3 60.269.2 61.169.3 ,0.001
BMI (kg/m2) 24.463.2 24.763.1 24.662.8 24.362.9 24.263.0 24.362.9 0.001
Waist circumference 90.7610.2 90.169.6 88.968.1 87.768.5 87.068.6 88.068.5 ,0.001
(cm)
Smoking (%) 6 (10.2) 28 (9.5) 199 (11.1) 675 (10.8) 75 (12.6) 983 (10.9) ,0.001
Alcohol intake (%) 13 (23.2) 85 (29.8) 702 (41.1) 2,799 (46.3) 293 (49.3) 3,892 (44.8) ,0.001
Physically active1 (%) 5 (8.9) 45 (15.4) 310 (17.3) 1,158 (18.8) 106 ( 18.3) 1,624 (18.3) 0.138
Hypertensive 45 (77.6) 188 (63.3) 848 (47.2) 1,992 (31.6) 148 (24.7) 3,221 (35.6) ,0.001
  medication (%)
Diabetes medication 19 (32.8) 80 (26.9) 296 (16.5) 701 (11.1) 66 (11.0) 1,162 (12.8) ,0.001
(%)
Total cholesterol 188.2640.8 193.1644.2 203.2642.3 201.1639.2 202.0638.4 201.2640.0 ,0.001
 (mg/dL)
Triglycerides (mg/dL) 144.8675.3 151.2690.4 149.3697.5 140.3696.4 147.96146.8 143.06100.5 0.004
HDL cholesterol 46.4610.9 48.4612.2 49.8611.4 52.0611.9 54.1612.9 51.6612.0 ,0.001
 (mg/dL)
PTH (pg/mL) 118.46110.5 57.9635.6 44.3619.5 41.7617.0 40.8617.9 43.2621.5 ,0.001
25(OH)D (ng/mL) 15.465.9 16.565.5 16.965.8 16.765.8 16.065.6 16.765.8 0.014
ACR 399.46508.6 110.16237.1 46.96141.4 29.7696.0 28.1675.1 38.16123.8 ,0.001
 (mg/mg creatinine)

All values are given as n (%) or mean6standard deviation.

BMI, body mass index; HDL, high-density lipoprotein; PTH, parathyroid hormone; 25(OH)D, 25-hydroxyvitamin D; ACR,
albumin/creatinine ratio.
1 
Subjects who performed 30 min or more of moderate activity at least 5 d a week or 20 min of vigorous physical activity at
least 3 d a week were regarded as doing physical activity.

Therefore, the present study assessed the associations
among PTH, estimated GFR (eGFR), and the albumin/
creatinine ratio (ACR) after adjusting for covariates in
an adult Korean population $50 y of age.
MATERIALS AND METHODS
Study population.  The Dong-gu Study is an ongoing
prospective population-based study investigating the
prevalence and incidence of, and risk factors for, chronic
disease in an elderly urban population. The Dong-gu
Study complies with all tenets of the Declaration of
Helsinki and was approved by the Institutional Review
Board (IRB) of Chonnam National University Hospi-
tal (No I-2008-05-056). All participants gave written
informed consent. Detailed information on the study
participants and the measurements performed in rela-
tion to this population have been previously published
(18). National resident registration records were used
to identify potential study participants. From 2007 to
2010, 34,040 eligible subjects aged $50 y who resided
in the Dong-gu district of Gwangju City in South Korea
(35˚N) were invited by telephone to participate in the
study, and 9,260 subjects were subsequently enrolled
(response rate: 27.2%; 3,713 males and 5,547 females).
After excluding 128 participants because of no vital
data (n5125) such as PTH or 25-hydroxyvitamin D
(25(OH)D) or serum creatinine, and a high urine albu-
min/creatinine ratio (n53, ACR$3,000 mg/g) indica-
tive of nephrotic-range albuminuria and altered vitamin
D metabolism (19), we included 9,132 subjects (3,653
males and 5,479 females) in the final analyses.
Data collection.  Trained examiners interviewed the
patients using a questionnaire that included items on
smoking, alcohol intake, physical activity, history of dia-
betes and hypertensive medication. Smoking status was
based on self-reported cigarette use: never-smokers had
smoked fewer than 100 cigarettes in their lifetime, and
participants who had smoked 100 or more cigarettes
were classified as past or current smokers based on their
current smoking habit. Alcohol intake was assessed
according to the participants’ drinking behavior dur-
ing the month prior to the interview. Physically active
was indicated as ‘yes’ when the participant performed
moderate or strenuous exercise on a regular basis (more
than 20 min at a time more than three times a week for
strenuous exercise or more than 30 min at a time more
than five times a week for moderate exercise). Weight
was measured to the nearest 0.1 kg while the subjects
were dressed in light clothing. Height was measured to
the nearest 0.1 cm in stocking feet. Body mass index
20 Choi SW et al.

Table  2.  Characteristics of the subjects according to ACR levels.

ACR (mg/mg creatinine)

Variable Total p value
,10 10–29 30–299 $300

N (%) 3,498 (38.3) 3,777 (41.4) 1,673 (18.3) 184 (2.0) 9,132 (100.0)
Male (%) 1,448 (41.4) 1,398 (37.0) 719 (43.0) 88 (47.8) 3,653 (40.0) ,0.001
Age (y) 63.267.6 65.767.9 67.768.7 67.768.0 65.168.2 ,0.001
Height (cm) 159.268.1 157.668.4 157.768.6 158.768.8 158.368.4 ,0.001
Weight (kg) 61.468.9 60.669.4 61.569.7 62.0610.3 61.169.3 ,0.001
BMI (kg/m2) 24.262.8 24.463.0 24.763.0 24.663.1 24.362.9 ,0.001
Waist circumference (cm) 87.568.3 87.968.8 89.068.5 89.769.1 88.068.5 ,0.001
Smoking (%) 380 (11.0) 410 (11.0) 166 (10.0) 27 (14.8) 983 (10.9) 0.002
Alcohol intake (%) 1,579 (47.2) 1,548 (43.1) 702 (44.3) 63 (36.6) 3,892 (44.8) 0.001
Physically active1 (%) 700 (20.5) 622 (17.0) 271 (16.6) 31 (17.4) 1,624 (18.3) ,0.001
Hypertensive medication (%) 1,011 (29.1) 1,313 (35.2) 789 (47.6) 108 (58.7) 3,221 (35.6) ,0.001
Diabetes medication (%) 231 (6.7) 455 (12.2) 387 (23.3) 89 (48.4) 1,162 (12.8) ,0.001
Total cholesterol (mg/dL) 198.5638.2 202.5639.4 203.3643.7 208.3646.7 201.2640.0 ,0.001
Triglycerides (mg/dL) 133.3686.0 142.4693.6 161.46134.8 170.06101.7 143.06100.5 ,0.001
HDL cholesterol (mg/dL) 51.6611.8 52.0611.9 50.8612.3 49.7612.8 51.6612.0 0.001
PTH (pg/mL) 40.2617.8 43.6617.9 46.9625.3 57.0663.1 43.2621.5 ,0.001
25(OH)D (ng/mL) 17.366.0 16.365.6 16.365.6 15.766.4 16.765.8 ,0.001
eGFR (mL/min per 1.73 m2) 70.8612.6 69.4613.0 66.0615.2 56.5620.9 69.1613.7 ,0.001

All values are given as n (%) or mean6standard deviation.

BMI, body mass index; HDL, high-density lipoprotein; PTH, parathyroid hormone; 25(OH)D, 25-hydroxyvitamin D; eGFR,
estimated glomerular filtration rate.
1 
Subjects who performed 30 min or more of moderate activity at least 5 d a week or 20 min of vigorous physical activity at
least 3 d a week were regarded as doing physical activity.

was calculated as weight in kilograms divided by the
square of the height in meters. Waist circumference
(WC) was measured with a flexible tape at the narrow-
est point between the lowest rib and the uppermost lat-
eral border of the right iliac crest. Blood samples were
drawn from antecubital veins following 12-h overnight
fasts; the sera were separated within 30 min, and sam-
ples were stored at 270˚C prior to analysis. The levels of
total cholesterol (TC), triglycerides (TG), and high-den-
sity lipoprotein (HDL) cholesterol were measured using
enzymatic methods on an automatic analyzer (Hita-
chi-7600; Hitachi, Ltd., Tokyo, Japan).
Measurement of serum concentrations of PTH and
25(OH)D.  Serum PTH and 25(OH)D levels were mea-
sured with the aid of a microparticle immunoassay
system that detected chemiluminescence (ARCHITECT
i2000; Abbott Diagnostics, Abbott Park, IL). In a com-
parative study of automated immunoassays and liquid
chromatography-tandem mass spectrometry methods
(LC-MS/MS) (20), the Abbott 25(OH)D assay was com-
parable to LC-MS/MS; the concordance correlation coef-
ficient was 0.85, and the mean bias was 4.56 ng/mL.
The coefficient of variation for the total analytic preci-
sion of the PTH assay was #9% and the lower detec-
tion limit was 1.0 pg/mL. The coefficient of variation for
the 25(OH)D assay was #10%, and the lower detection
limit was 3.0 ng/mL. According to the manufacturer’s
specifications, the assay has 105% cross-reactivity with
25(OH)D3, 82% cross-reactivity with 25(OH)D2, 12.6%
cross-reactivity with 1,25(OH)2D3, 112% cross-reactiv-
ity with 24,25(OH)2D3, and minimal cross-reactivity
with 3-epimer of 25(OH)D3 (2.7%). Hypovitaminosis D
was defined as a level of ,15 ng/mL and hyperparathy-
roidism was defined as a level of .65 pg/mL, based on a
previous study (21).
Measurement of kidney function.  Kidney function
was assessed by eGFR, which was calculated with the
Chronic Kidney Disease Epidemiology Collaboration
(CKD-EPI) equation as follows (22):
eGFRCKD-EPI51 413 min(Scr/ k , 1) a 3 max(Scr/ k ,
1)21.20930.993Age31.018 (if female),
where age is in years, Scr is serum creatinine in mil-
ligrams per deciliter, k is 0.7 for females and 0.9 for
males, a is 20.329 for females and −0.411 for males,
min indicates the minimum of Scr/k or 1, and max indi-
cates the maximum of Scr/k or 1.
Urinary albumin and creatinine concentrations were
measured using a turbidimetric immunoassay and the
Jaffe method (23) with a Hitachi-7600 analyzer (Hita-
chi, Ltd.). Albuminuria was defined according to the
ACR, which was calculated by dividing the urinary
albumin concentration (mg) by the urinary creatinine
concentration (mg).
Statistical analysis.  Data are presented as means6
standard deviations (SDs) or as percentages by the
eGFR levels (,30, 30–44, 45–59, 60–89, $90 mL/min
per 1.73 m2) and ACR levels (,10, 10–29, 30–299,
$300  mg/mg creatinine). Analysis of covariance
(ANCOVA) was used to compare the PTH value stratified
by 25(OH)D levels (#10.0, 10.1–20.0, .20.0 ng/mL)
 Parathyroid Hormone Levels Associated with eGFR and Albuminuria 21

Table  3.  Comparison of PTH values stratified by 25(OH)D levels according to eGFR levels.

Model 1 Model 2
25(OH)D level eGFR level
(ng/mL) (mL/min per 1.73 m2)
Mean (95% CI) Mean (95% CI)

,30 173.3 (148.9–197.7) 169.2 (144.5–193.9)

30–44 77.8 (66.5–89.1) 77.1 (65.8–88.4)
45–59 50.9 (45.7–56.1) 50.8 (45.7–56.0)
#10.0 60–89 51.5 (48.8–54.2) 51.6 (48.9–54.3)
$90 54.8 (46.9–62.8) 54.9 (46.9–62.8)
p ,0.001 ,0.001

,30 133.9 (127.5–140.4) 131.6 (125.2–138.1)

30–44 56.3 (53.4–59.3) 55.7 (52.8–58.7)
45–59 44.7 (43.5–45.9) 44.6 (43.4–45.8)
10.1–20.0 60–89 42.3 (41.7–42.9) 42.4 (41.7–43.0)
$90 41.5 (39.5–43.5) 41.3 (39.3–43.3)
p ,0.001 ,0.001

,30 56.6 (48.0–65.2) 55.3 (46.6–63.9)

30–44 46.6 (43.0–50.3) 45.8 (42.2–49.5)
45–59 38.5 (37.0–39.9) 38.4 (36.9–39.9)
.20.0 60–89 36.8 (36.0–37.6) 36.9 (36.1–37.7)
$90 36.5 (33.7–39.3) 36.5 (33.7–39.2)
p ,0.001 ,0.001

All values are given as mean (95%CI).

25(OH)D, 25-hydroxyvitamin D; eGFR, estimated glomerular filtration; ACR, albumin/creatinine ratio.
Model 1: Adjusted by sex, age, waist circumference, smoking, alcohol intake, physical activity, hypertension medications,
diabetes medication, hyperlipidemia medication, total cholesterol, triglyceride and HDL cholesterol.
Model 2: Adjusted by Model 1 plus log-ACR.

according to eGFR and ACR levels.
The eGFR, ACR and 25(OH)D data were not distrib-
uted normally; thus, to approximate normal distribu-
tions, the eGFR, ACR and 25(OH)D data were log-trans-
formed prior to ANCOVA. Model 1 was adjusted for sex,
and age, waist circumference, smoking, alcohol intake,
physical activity, hypertensive medications, diabetes
medication, total cholesterol, triglyceride, and HDL cho-
lesterol levels. Model 2 included the variables of Model
1 and the log-ACR or log-eGFR. All statistical analy-
ses were performed using SPSS software version 18.0
(SPSS, Inc., Chicago, IL). A p-value ,0.05 was consid-
ered to reflect statistical significance.
RESULTS
Characteristics of subjects according to eGFR levels
The characteristics of the 9,132 subjects according to
eGFR levels included in the study are shown in Table 1.
Higher eGFR levels tended to be associated with higher
levels of alcohol intake, and higher HDL cholesterol.
Moreover, higher eGFR levels were associated with a
lower percentage of male subjects, younger age, lower
height, weight, and waist circumference, lower use of
hypertensive medication and diabetes medication, and
lower PTH and ACR.
Characteristics of subjects according to ACR levels
The characteristics of the subjects according to ACR
levels are shown in Table 2. Higher ACR levels tended to
be associated with older age, higher BMI and waist cir-
cumference, higher use of hypertensive medication and
diabetes medication, and higher TC, TG, and PTH. More-
over, higher ACR levels were associated with a lower
level of alcohol intake and lower 25(OH)D and eGFR.
Comparison of PTH values stratified by 25(OH)D levels
according to eGFR levels
The PTH values (95% confidence interval (CI)) strati-
fied by 25(OH)D levels according to eGFR levels are
shown in Table 3. After adjusting for covariates (sex, age,
waist circumference, smoking, alcohol intake, physical
activity, hypertension medications, diabetes medication,
total cholesterol, triglyceride, HDL cholesterol and log-
ACR) (Model 2), the PTH value significantly decreased
with increasing eGFR levels in each 25(OH)D stratum.
Comparison of PTH values stratified by 25(OH)D levels
according to ACR levels
The PTH value (95% CI) stratified by 25(OH)D levels
according to ACR levels are shown in Table 4. After
adjusting for covariates (Model 2), the PTH value sig-
nificantly increased with increasing ACR levels in each
25(OH)D stratum.
Distribution of PTH value according to eGFR and ACR lev-
els, and to 25(OH)D and ACR levels
Figure 1 shows the distribution of PTH values accord-
ing to eGFR and ACR levels, and to 25(OH)D and ACR
levels. When the PTH values were compared according
to eGFR and ACR levels, the PTH values were lowest at
22 Choi SW et al.

Fig.  1.  Distribution of PTH values according to eGFR and ACR levels (A), and to 25(OH)D and ACR levels (B).

Table  4.  Comparison of PTH values stratified by 25(OH)D levels according to ACR levels.

Model 1 Model 2
25(OH)D level ACR level
(ng/mL) (mg/mg creatinine)
Mean (95% CI) Mean (95% CI)

,10 51.1 (46.7–55.4) 51.1 (46.8–55.3)

10–29 51.2 (47.6–54.7) 52.0 (48.6–55.5)
#10.0 30–299 59.3 (54.0–64.5) 59.4 (54.3–64.5)
$300 78.3 (64.8–91.7) 65.3 (51.4–79.2)
p ,0.001 0.029

,10 41.1 (40.2–42.0) 41.3 (40.4–42.1)

10–29 43.7 (42.9–44.5) 44.1 (43.3–44.9)
10.1–20.0 30–299 47.3 (46.0–48.6) 46.8 (45.6–48.0)
$300 60.0 (56.1–64.0) 53.5 (49.7–57.4)
p ,0.001 ,0.001

,10 36.1 (35.1–37.1) 36.2 (35.2–37.2)

10–29 37.9 (36.8–39.0) 37.9 (36.9–39.0)
.20.0 30–299 40.2 (38.5–41.8) 39.9 (38.3–41.5)
$300 45.5 (40.4–50.6) 44.2 (39.1–49.3)
p ,0.001 ,0.001

All values are given as mean (95%CI).

25(OH)D, 25-hydroxyvitamin D; eGFR, estimated glomerular filtration; ACR, albumin/creatinine ratio.
Model 1: Adjusted by sex, age, waist circumference, smoking, alcohol intake, physical activity, hypertension medications,
diabetes medication, hyperlipidemia medication, total cholesterol, triglyceride and HDL cholesterol.
Model 2: Adjusted by Model 1 plus log-eGFR.

the highest eGFR level ($90.0 mL/min/1.73 m2) and
the lowest ACR level (,10  mg/mg creatinine). The PTH
values were highest at the lowest eGFR level (,30.0 mL/
min/1.73 m2) and the highest ACR level ($300  mg/mg
creatinine).
When the PTH values were compared according to
25(OH)D and ACR levels, the PTH values were lowest at
the highest 25(OH)D level (.20 ng/mL) and the lowest
ACR level (,10  mg/mg creatinine). The PTH values were
highest at the lowest 25(OH)D level (#10.0 ng/mL) and
the highest ACR level ($300  mg/mg creatinine).
Hypovitaminosis, hyperparathyroidism, and hypovitamino-
sis with hyperparathyroidism according to eGFR levels
Figure 2 shows the percentage of hypovitaminosis D,
hyperparathyroidism, and hypovitaminosis with hyper-
parathyroidism according to eGFR levels. In all subjects,
the percentage of hypovitaminosis D, hyperparathyroid-
ism, and hypovitaminosis with hyperparathyroidism was
44.2%, 9.8%, and 6.1%, respectively. The percentage of
hypovitaminosis D was highest (55.9%) in subjects with
eGFR ,30 mL/min per 1.73 m2 and tended to stay at
approximately 40% with increasing eGFR level. The per-
centage of hyperparathyroidism tended to decrease with
increasing eGFR level (,30: 64.4%; 30–44: 30.7%;
45–59: 12.3%; 60–89: 7.7%; $90: 7.9%). The per-
centage of subjects with both hypovitaminosis D and
hyperparathyroidism tended to decrease with increasing
eGFR level (,30: 40.7%; 30–44: 17.0%; 45–59: 7.7%;
60–89: 4.8%; $90: 6.1%).
DISCUSSION
We investigated the association of PTH with eGFR
and ACR in an adult Korean population aged $50 y.
The PTH value significantly decreased with increasing
 Parathyroid Hormone Levels Associated with eGFR and Albuminuria
Fig.  2.  Percentage of hypovitaminosis [25(OH)D,15 ng/mL], hyperparathyroidism (PTH.65 pg/mL), and hypovitamin-
osis with hyperparathyroidism according to eGFR levels.
eGFR levels independently of 25(OH)D. The PTH value
significantly increased with increasing ACR levels inde-
pendently of 25(OH)D.
Most previous studies were conducted with a medical
database of hospital patients (24) or with CKD patients
(25, 26) and showed a robust association between eGFR
and PTH. The mechanism of the relationship between
eGFR and PTH in renal deficiency is well documented.
As kidney function declines, levels of plasma phos-
phate increase while levels of plasma calcium and
1,25(OH)2D decrease. A reduction in 1,25(OH)2D also
contributes to a reduction in intestinal calcium absorp-
tion. All of these factors contribute to the development
of hypocalcemia, which is the impetus for an increased
production of PTH (16). However, in our data, strati-
fication by 25(OH)D level revealed that PTH value
decreased significantly with increasing eGFR levels
in every 25(OH)D level. Our findings indicate that the
relationship between PTH and eGFR may be mediated
by a 25(OH)D-independent mechanism. Impaired renal
function causes the increase of fibroblast growth fac-
tor-23 (FGF-23) in part due to a consequence of phos-
phate retention, but also due to decreased renal clear-
ance of FGF-23 (27, 28), and FGF-23 directly decreases
PTH mRNA expression and protein secretion (29, 30).
Moreover, in our analysis, the negative association
between eGFR and PTH was significant in subjects with
eGFR ,60 but also in subjects with eGFR $60 mL/
min per 1.73 m2. In a study with non-nephrotic ure-
mic patients (31), PTH concentrations were negatively
correlated with GFR (r520.57, p,0.001) and median
PTH (range) values were increased with decreasing GFR
[5.6 (2.2–13.0) in GFR 60–90, 8.1 (2.9–24.0) in GFR
40–60, and 13.0 (5.4–59.0) in GFR 20–40 mL/min per
1.73 m2]. In the study by the Korea National Health and
Nutrition Examination Survey (32), PTH was negatively
23
associated with eGFR in the general population, similar
to our results.
In the present study, PTH values stratified by 25(OH)
D level was positively associated with ACR. To the best
of our knowledge, the direct relationship between PTH
and ACR has rarely been investigated. In a study of
CKD patients (25), patients with higher PTH had higher
24-h urine protein (p,0.001). In addition, in the analy-
sis from the Kidney Early Evaluation Program (KEEP)
(26), the prevalence of microalbuminuria and mac-
roalbuminuria increased with increasing PTH levels
(p,0.001), similar to our results. Several mechanisms
may underlie the association between PTH and ACR.
Hypovitaminosis D raises the PTH concentration, and
increases the ACR level by activating the renin-angio-
tensin system (33) and the nuclear factor-kB (NF-kB)
pathway (34), increasing podocyte apoptosis (35). How-
ever, our findings indicate that PTH was related with
ACR via a 25(OH)D-independent mechanism; higher
PTH raises intracellular calcium in target tissues and is
related to vascular calcification (36) and left ventricu-
lar hypertrophy (12). Additionally, PTH might have a
prosclerotic effect on vascular smooth muscle cells (37)
and is associated with increased arterial stiffness and
intrarenal arterial resistance (38), which contribute
to vascular endothelial damage within the glomerular
basement membrane, thus leading to the excretion of
albumin into the urine (39).
In the present study, the percentage of hyperparathy-
roidism tended to decrease with increasing eGFR levels
and that of hypovitaminosis D tended to stay at approxi-
mately 40% with increasing eGFR levels. Moreover, the
subjects with both hyperparathyroidism and hypovita-
minosis D were only one of seven among the subjects
with hypovitaminosis D. This is surprising; previous
studies have explained the associations between vitamin
24 Choi SW et al.
D and PTH by citing the hypovitaminosis D and second-
ary hyperparathyroidism pathway (40). We do not know
the exact mechanism by which high hypovitaminosis
D and low hyperparathyroidism may be related in our
subjects, but these may be partially explained by ethnic
backgrounds. In an analysis of race and ethnicity, the
PTH value was lower among Asian people (41). Notably,
South Korean people showed the highest level of hypo-
vitaminosis D and the lowest level of PTH among 18
countries (17). In addition, hypovitaminosis D is not the
only determinant of hyperparathyroidism. The develop-
ment of secondary hyperparathyroidism results from
many factors, including a deficiency of 1a,25(OH)2D,
phosphate retention (42), low serum Ca21 (11), and a
decrease in the activation of vitamin D receptors (VDRs)
and calcium-sensing receptors (CaRs) in the parathy-
roid gland (43).
The primary strengths of our study lie in its popula-
tion-based design and the use of a relatively large sam-
ple size, which minimized selection bias and provided
sufficient statistical power. However, the study has sev-
eral limitations. First, because we used a cross-sectional
design, the ability to establish a causal relationship
between PTH, eGFR and ACR is limited. Second, because
only one serum PTH measurement was taken, our find-
ings reflect a single point in time rather than long-term
exposure. Second, we used a single morning spot urine
sample to assess microalbuminuria, instead of timed
urine collections, which would have been preferable.
However, early morning urine provides a good estimate
of 24-h urinary albumin excretion rates, and a urinary
ACR of .3.0 mg/mmol is associated with an albumin
excretion rate of .30 mg/min, with high sensitivity
and specificity (44).
In conclusion, the PTH values significantly decreased
with increasing eGFR levels and increased with increas-
ing ACR levels independently of 25(OH)D in an adult
Korean population $50 y of age.
REFERENCES
1) Coresh J, Selvin E, Stevens LA, Manzi J, Kusek JW, Egg-
ers P, Van Lente F, Levey AS. 2007. Prevalence of
chronic kidney disease in the United States. JAMA 298:
2038–2047.
2) National Kidney Foundation. 2002. K/DOQI clinical
practice guidelines for chronic kidney disease: evalua-
tion, classification, and stratification. Am J Kidney Dis
39: S1–266.
3) De Leeuw PW, Thijs L, Birkenhäger WH, Voyaki SM,
Efstratopoulos AD, Fagard RH, Leonetti G, Nachev C,
Petrie JC, Rodicio JL, Rosenfeld JJ, Sarti C, Staessen JA,
Systolic Hypertension in Europe (Syst-Eur) Trial Investi-
gators. 2002. Prognostic significance of renal function
in elderly patients with isolated systolic hypertension:
results from the Syst-Eur trial. J Am Soc Nephrol 13:
2213–2222.
4) Shlipak MG, Simon JA, Grady D, Lin F, Wenger NK, Fur-
berg CD, Heart and Estrogen/progestin Replacement
Study (HERS) Investigators. 2001. Renal insufficiency
and cardiovascular events in postmenopausal women
with coronary heart disease. J Am Coll Cardiol 38:
705–711.
5) Muntner P, He J, Hamm L, Loria C, Whelton PK. 2002.
Renal insufficiency and subsequent death resulting from
cardiovascular disease in the United States. J Am Soc
Nephrol 13: 745–753.
6) Gerstein HC, Mann JF, Yi Q, Zinman B, Dinneen SF, Hoog-
werf B, Hallé JP, Young J, Rashkow A, Joyce C, Nawaz S,
Yusuf S, HOPE Study Investigators. 2001. Albuminuria
and risk of cardiovascular events, death, and heart fail-
ure in diabetic and nondiabetic individuals. JAMA 286:
421–426.
7) Hunsicker LG, Adler S, Caggiula A, England BK, Greene
T, Kusek JW, Rogers NL, Teschan PE. 1997. Predictors of
the progression of renal disease in the Modification of
Diet in Renal Disease Study. Kidney Int 51: 1908–1919.
8) Ruggenenti P, Perna A, Mosconi L, Pisoni R, Remuzzi
G. 1998. Urinary protein excretion rate is the best
independent predictor of ESRF in non-diabetic protein-
uric chronic nephropathies. “Gruppo Italiano di Studi
Epidemiologici in Nefrologia” (GISEN). Kidney Int 53:
1209–1216.
9) Goolsby MJ. 2002. National Kidney Foundation Guide-
lines for chronic kidney disease: evaluation, classifi-
cation, and stratification. J Am Acad Nurse Pract 14:
238–242.
10) Calvo G, de Andres-Trelles F. 2004. Albuminuria as a
surrogate marker for drug development: a European
regulatory perspective. Kidney Int Suppl 92: S126–127.
11) Lee M, Partridge NC. 2009. Parathyroid hormone sig-
naling in bone and kidney. Curr Opin Nephrol Hypertens
18: 298–302.
12) Nainby-Luxmoore JC, Langford HG, Nelson NC, Wat-
son RL, Barnes TY. 1982. A case-comparison study of
hypertension and hyperparathyroidism. J Clin Endocrinol
Metab 55: 303–306.
13) Ahlström T, Hagström E, Larsson A, Rudberg C, Lind L,
Hellman P. 2009. Correlation between plasma calcium,
parathyroid hormone (PTH) and the metabolic syn-
drome (MetS) in a community-based cohort of men and
women. Clin Endocrinol (Oxf) 71: 673–678.
14) Smith DH, Johnson ES, Thorp ML, Yang X, Neil N. 2009.
Hyperparathyroidism in chronic kidney disease: a ret-
rospective cohort study of costs and outcomes. J Bone
Miner Metab 27: 287–294.
15) Uhlig K, Berns JS, Kestenbaum B, Kumar R, Leonard
MB, Martin KJ, Sprague SM, Goldfarb S. 2010. KDOQI
US commentary on the 2009 KDIGO clinical practice
guideline for the diagnosis, evaluation, and treatment of
CKD–mineral and bone disorder (CKD-MBD). Am J Kid-
ney Dis 55: 773–799.
16) Felsenfeld A, Silver J. 2006. Pathophysiology and clini-
cal manifestations of renal osteodystrophy. In: Clinical
Guide to Bone and Mineral Metabolism in CKD (Olgaard
K, ed), p 31–41. National Kidney Foundation, New York.
17) Lips P, Hosking D, Lippuner K, Norquist JM, Wehren L,
Maalouf G, Ragi-Eis S, Chandler J. 2006. The prevalence
of vitamin D inadequacy amongst women with osteopo-
rosis: an international epidemiological investigation. J
Intern Med 260: 245–254.
18) Kweon SS, Shin MH, Jeong SK, Nam HS, Lee YH, Park
KS, Ryu SY, Choi SW, Kim BH, Rhee JA, Zheng W, Choi
JS. 2014. Cohort profile: The Namwon Study and the
Dong-gu Study. Int J Epidemiol 43: 558–567.
19) Saha H. 1994. Calcium and vitamin D homeostasis
in patients with heavy proteinuria. Clin Nephrol 41:
290–296.
 Parathyroid Hormone Levels Associated with eGFR and Albuminuria
20) Farrell C-JL, Martin S, McWhinney B, Straub I, Wil-
liams P, Herrmann M. 2012. State-of-the-art vitamin
D assays: a comparison of automated immunoassays
with liquid chromatography-tandem mass spectrometry
methods. Clin Chem 58: 531–542.
21) Levin A, Bakris GL, Molitch M, Smulders M, Tian J, Wil-
liams LA, Andress DL. 2007. Prevalence of abnormal
serum vitamin D, PTH, calcium, and phosphorus in
patients with chronic kidney disease: results of the study
to evaluate early kidney disease. Kidney Int 71: 31–38.
22) Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF,
Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T,
Coresh J, Ckd EPI. 2009. A new equation to estimate glo-
merular filtration rate. Ann Intern Med 150: 604–612.
23) Lustgarten JA, Wenk RE. 1972. Simple, rapid, kinetic
method for serum creatinine measurement. Clin Chem
18: 1419–1422.
24) Patel S, Barron JL, Mirzazedeh M, Gallagher H, Hyer S,
Cantor T, Fraser WD. 2011. Changes in bone mineral
parameters, vitamin D metabolites, and PTH measure-
ments with varying chronic kidney disease stages. J Bone
Miner Metab 29: 71–79.
25) Kovesdy CP, Ahmadzadeh S, Anderson JE, Kalantar-
Zadeh K. 2008. Secondary hyperparathyroidism is
associated with higher mortality in men with moder-
ate to severe chronic kidney disease. Kidney Int 73:
1296–1302.
26) Bhuriya R, Li S, Chen S-C, McCullough PA, Bakris GL.
2009. Plasma parathyroid hormone level and prevalent
cardiovascular disease in CKD stages 3 and 4: an analy-
sis from the Kidney Early Evaluation Program (KEEP).
Am J Kidney Dis 53: S3–10.
27) Larsson T, Nisbeth U, Ljunggren O, Jüppner H, Jons-
son KB. 2003. Circulating concentration of FGF-23
increases as renal function declines in patients with
chronic kidney disease, but does not change in response
to variation in phosphate intake in healthy volunteers.
Kidney Int 64: 2272–2279.
28) Weber TJ, Liu S, Indridason OS, Quarles LD. 2003.
Serum FGF23 levels in normal and disordered phospho-
rus homeostasis. J Bone Miner Res 18: 1227–1234.
29) Ben-Dov IZ, Galitzer H, Lavi-Moshayoff V, Goetz R, Kuro-
o M, Mohammadi M, Sirkis R, Naveh-Many T, Silver J.
2007. The parathyroid is a target organ for FGF23 in
rats. J Clin Invest 117: 4003–4008.
30) Krajisnik T, Björklund P, Marsell R, Ljunggren O, Aker-
ström G, Jonsson KB, Westin G, Larsson TE. 2007. Fibro-
blast growth factor-23 regulates parathyroid hormone
and 1alpha-hydroxylase expression in cultured bovine
parathyroid cells. J Endocrinol 195: 125–131.
31) Reichel H, Deibert B, Schmidt-Gayk H, Ritz E. 1991. Cal-
cium metabolism in early chronic renal failure: impli-
cations for the pathogenesis of hyperparathyroidism.
Nephrol Dial Transplant 6: 162–169.
32) Han SW, Kim SJ, Lee DJ, Kim KM, Joo NS. 2014. The
25
relationship between serum 25-hydroxyvitamin D, para-
thyroid hormone and the glomerular filtration rate in
Korean adults: The Korea National Health and Nutrition
Examination Survey between 2009 and 2011. Korean J
Fam Med 35: 98–106.
33) Li YC, Qiao G, Uskokovic M, Xiang W, Zheng W, Kong J.
2004. Vitamin D: a negative endocrine regulator of the
renin–angiotensin system and blood pressure. J Steroid
Biochem Mol Biol 89-90: 387–392.
34) Sun J, Kong J, Duan Y, Szeto FL, Liao A, Madara JL, Li YC.
2006. Increased NF-kB activity in fibroblasts lacking the
vitamin D receptor. Am J Physiol Endocrinol Metab 291:
E315–322.
35) Kuhlmann A, Haas CS, Gross ML, Reulbach U, Holz-
inger M, Schwarz U, Ritz E, Amann K. 2004. 1,25-Dihy-
droxyvitamin D3 decreases podocyte loss and podocyte
hypertrophy in the subtotally nephrectomized rat. Am J
Physiol Renal Physiol 286: F526–533.
36) Massry SG, Smogorzewski M. 1994. Mechanisms
through which parathyroid hormone mediates its del-
eterious effects on organ function in uremia. Semin
Nephrol 14: 219–231.
37) Perkovic V, Hewitson TD, Kelynack KJ, Martic M, Tait
MG, Becker GJ. 2003. Parathyroid hormone has a pro-
sclerotic effect on vascular smooth muscle cells. Kidney
Blood Press Res 26: 27–33.
38) Trovato GM, Martines GF, Trovato FM, Pirri C, Pace P,
Catalano D. 2012. Renal resistive index and parathyroid
hormone relationship with renal function in nondia-
betic patients. Endocr Res 37: 47–58.
39) Deen WM. 2004. What determines glomerular capillary
permeability? J Clin Invest 114: 1412–1414.
40) Sahota O, Mundey MK, San P, Godber IM, Lawson N,
Hosking DJ. 2004. The relationship between vitamin
D and parathyroid hormone: calcium homeostasis,
bone turnover, and bone mineral density in postmeno-
pausal women with established osteoporosis. Bone 35:
312–319.
41) De Boer IH, Gorodetskaya I, Young B, Hsu CY, Chertow
GM. 2002. The severity of secondary hyperparathyroid-
ism in chronic renal insufficiency is GFR-dependent,
race-dependent, and associated with cardiovascular dis-
ease. J Am Soc Nephrol 13: 2762–2769.
42) McCarthy JT, Kumar R. 1986. Behavior of the vitamin D
endocrine system in the development of renal osteodys-
trophy. Semin Nephrol 6: 21–30.
43) Ritter CS, Martin DR, Lu Y, Slatopolsky E, Brown AJ.
2002. Reversal of secondary hyperparathyroidism by
phosphate restriction restores parathyroid calcium-
sensing receptor expression and function. J Bone Miner
Res 17: 2206–2213.
44) Hutchison AS, O’Reilly DS, MacCuish AC. 1988. Albu-
min excretion rate, albumin concentration, and albu-
min/creatinine ratio compared for screening diabetics
for slight albuminuria. Clin Chem 34: 2019–2021.