Association between Parathyroid

Hormone, 25 (OH) Vitamin D, and

Chronic Kidney Disease: A
Population-Based Study
GRUPO D

Wei-Hao Wang, Li-Wei Chen, Chin-Chan Lee, Chiao-Yin Sun, Yu-Chiau Shyu, Heng-
Rong Hsu, Rong-Nang Chien, and I-Wen Wu.
Received 2016 Nov 4; Revised 2017 Jan 25; Accepted 2017 Feb 14.

NLM NIH DHHS USA.gov

National Center for Biotechnology Information, U.S. National Library of Medicine
INTRODUCTION

Chronic kidney disease (CKD) is a worldwide public health

issue because of its wide association with multiple
comorbidities, demanding high cardiovascular events,
mortality, and expensive medical cost. The worldwide
prevalence of CKD ranged from 8 to 16%, dependent on the
disease definition, study design, and racial groups.

The associations of CKD with several traditional risk factors

(such as hypertension, diabetes, obesity, smoking,
dyslipidemia, and metabolic syndrome) were well
established.
Epidemiological literatures emphasized the association
between serum vitamin D level and nonskeletal disease as
cardiovascular events, metabolic syndrome, cancer,
autoimmune disease, and critical illness. The decrease of
glomerular filtration rate restricts delivery of substrate to the
1-alpha-hydroxylase and decreases the production of 1,25 (OH)
vitamin D by the kidney in CKD patients.

The interplay between vitamin D, fibroblast growth factor-23

(FGF-23), intact parathyroid hormone (PTH), and calcium-
phosphorus-bone metabolism is disrupted with the progression
of renal function [1315]. However, the relationship between
vitamin D, intact PTH, and calcium-phosphate metabolism
and development of CKD remains controversial.
A Korean population-based study found a biphasic change of serum
vitamin D levels, according to CKD severity. The estimated glomerular
filtration rate (eGFR) was negatively associated with serum vitamin D
levels [16] in the entire population; however, the mean vitamin D values
were decreased with the lowering of eGFR levels in moderate and severe
CKD stages.
A Swiss population study did not find any association between serum
vitamin D levels and CKD or albuminuria [18]. In addition, the
association between vitamin D levels and renal function decline was lost
after adjustment for baseline eGFR. Accumulating evidence indicated the
association of abnormal calcium-phosphate metabolism with
cardiovascular disease in the general population.

Intact PTH levels were associated with hypertension [20] and abnormal
calcium-phosphate metabolism was associated with coronary artery
calcification.
METHOD

Participants of community health activity from August 2013 to May 2016

in the northeastern region of Taiwan were enrolled in the study.
Participants aged greater than 30 years and who were not pregnant were
included after obtaining informed consent (n = 4916). Individuals who
had received vitamin D supplementation or any over-the-counter vitamin
supplements (n = 830) or incomplete baseline biochemistry data (n = 6)
were excluded from the analysis.

Blood samples were obtained after an overnight fast, and the following
parameters were determined: complete blood cell count, liver and renal
biochemistry parameters, lipid profiles, fasting sugar, and intact PTH
and total 25 (OH) vitamin D levels.
A total of 4080 participants were included in the analysis. The mean age
was 58.4 13.3 years and 1480 (36.3%) were men. The mean eGFR of the
study population was 94.1 26.3 mL/min/1.73 m2. The overall prevalence of
CKD was 19.8%.

CKD patients were more likely to be older, to be male, and to be obese. They
were more likely to have diabetes, hypertension, metabolic syndrome, and
smoking/drinking habits. CKD patients had higher serum 25 (OH) vitamin
D [31.1 10.5 ug/mL versus 29.0 9.0 ug/mL, p < 0.001] and higher intact
PTH [46.3 (8.3, 898.9) pmol/L versus 42.2 (3.0, 311.2) pmol/L, p < 0.001]
levels than normal.
Serum 25 (OH) vitamin D (r = 0.212, p < 0.001), log intact PTH (r =
0.121, p < 0.001), and calcium (r = 0.079, p < 0.001) were inversely
correlated with eGFR, while phosphate (r = 0.116, p < 0.001) was
positively correlated with eGFR.

However, serum 25 (OH) vitamin D (r = 0.016, p = 0.259), log intact PTH

(r = 0.142, p < 0.001), calcium (r = 0.038, p = 0.030), and phosphate (r =
0.005, p = 0.665) were positively correlated with log albuminuria-to-
creatinine ratio.

Logistic regression analysis identified the log intact PTH as an

independent factor associated with CKD.

Again, log intact PTH was an independent factor associated with

proteinuria.
 To control as much as possible the confounding effect of baseline
characteristics of patients on the outcome of study, we have
resampled a subset of patients from stratified sampling by CKD
stage with individualized match to age, gender, presence of
hypertension, or metabolic syndrome. Stratified sampling by CKD
stage identified 464 CKD patients with their matched counterparts
(n = 928 normals). Only 1392 patients were included in the subset
analysis after individualized matched pair of 1 y/o of age. The mean
age of resampling subset was 61.0 10.9 years and 39% of them were
men. Hypertension was present in 73% and metabolic syndrome was
present in 43% of the resampling population. Both the log intact PTH
and hyperparathyroidism remained a significant risk factor for eGFR
60 mL/min and albuminuria, after adjustment for age, gender,
serum 25 (OH) vitamin D, and calcium or phosphate levels.
This community-based study found that the serum PTH levels were
inversely correlated with eGFR but positively correlated with albuminuria.
Either the increase of serum PTH levels or the presence of
hyperparathyroidism was independently associated with the risk of CKD,
after adjustments for confounders or by using the resampling subset of
comparable baseline characteristics. The serum PTH levels increased in the
early stage of CKD, before the change of 25 (OH) vitamin D-calcium-
phosphate axis, and may serve as a potential risk factor for CKD.

Growing evidence indicated the relationship between abnormal vitamin D

levels and metabolic syndrome, diabetes, cancer, and chronic diseases;
however, the association of vitamin D and the risk of CKD remains
controversial.
They did not find any significant association of serum vitamin D levels with
incident CKD, incident albuminuria, or rapid renal function decline, after a
mean follow-up of 5.5 years [19]. On the other hand, findings from the 10-
year Prevention of Renal and Vascular End-Stage Disease prospective cohort
demonstrated that low plasma vitamin D was associated with the risk of
developing albuminuria rather than reduced eGFR in high sodium intake
individuals.

Several factors can influence serum levels of vitamin D, including analytic

method, seasonal variation, latitude, air pollution, sun exposure, and
physical activity.
Molecularly, parathyroid hormone is considered as procalcific and profibrotic
through promoting mRNA and protein expression of the receptor of advanced
glycation end products (RAGE) and interleukin 6, enhancing abnormal
calcium-phosphate homeostasis and renin-angiotensinogen-aldosterone
hyperactivity; even some have advocated its possible roles as cardiovascular
or uremic toxins.

On the other hand, treatment of teriparatide (human PTH) in low-density

lipoprotein receptor mice exhibited induction of osseous osteopontin
expression and serum osteopontin levels, indicating inhibition of vascular
calcification and aortic osteogenic differentiation.

The study suggested possible beneficial actions of PTH at early stages of

macrovascular disease in responses to diabetes and dyslipidemia.
 In spite of the promising results of our study, caution in the interpretation
of PTH as a powerful biomarker should be taken into account, including
intermethod and interpersonal variability, target metabolite to measure,
vitamin D status, baseline renal function, age, gender, menopausal status,
body mass index, race, and end-organ hyporesponsiveness.
A peculiar finding of the present study was the elevated odd ratio of having
eGFR < 60 mL/min associated with serum calcium levels, even after
considering confounders. However, this association was no longer existent
when the serum calcium level was assessed in a categorical manner.
Physiologically, serum calcium levels decrease with the decline of eGFR. This
phenomenon appears in the late stage of CKD and contributes in part to the
hyperparathyroidism cascade leading to the development of CKD-bone
mineral disease and adverse patient outcomes.

Conversely, high serum calcium levels promote neointimal calcification and

increase cardiovascular events and mortality.

A French multicentric study found that increased serum calcium

concentration was independently and positively associated with high pulse
pressure and hypertension, an important risk factor for CKD.
CONCLUSION

In conclusion, this community-based study confirmed the association

of serum levels of PTH and hyperparathyroidism with the risk of
CKD. The serum levels of PTH increased in parallel with
albuminuria but inversely with eGFR.
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GRACIAS
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