Abstract
Molecular evidence suggest that sufficient 25[OH]D levels could
protect against renal function loss, but population-based studies
on the association of 25[OH]D with change in estimated glomerular
filtration rate (eGFR) and incident chronic kidney disease (CKD)
are limited and results discordant. No study explored the potential
effect modification of VDR genetic variants on the relationship
between 25[OH]D and change in kidney function. We used
cross-sectional data from the 2010-2011 Swiss Study on Salt intake
to compare the 25[OH]D levels, deficiency status and 25[OH]D level
determinants in populations without CKD and with CKD. We tested the
interaction of CKD status with six a priori defined attributes on
vitamin D. We used baseline (2003-2006) and 5-year follow-up data
(CoLaus study) of adults from the general population to evaluate
the association of serum 25[OH]D with change in kidney function,
rapid decline in kidney function, and incidence of CKD. Ten genetic
polymorphisms, of which five were within the VDR gene, were
considered a priori. We found that vitamin D insufficiency or
deficiency (25(OH)D<30 ng/ml) was frequent among participants
with CKD (74.8%, 95%CI 58.4-92.8) but neither the prevalence of
vitamin D insufficiency/deficiency nor the mean 25(OH)D levels were
different in patients with and without CKD. CKD status did not
interact with major determinants of vitamin D for its effect on
vitamin D status or levels. We found that annual eGFR change was
associated with baseline vitamin D levels and that higher baseline
vitamin D level was associated with decreased risk of rapid decline
in eGFR. We found a significant Cdx2 VDR genotype-25(OH)D
interaction on the risk of rapid eGFR decline or incident CKD
(P-value for interaction=0.022). Among participants with the Cdx2
VDR risk allele (CT/TT genotype), the adjusted ROR was 1.17 (95%CI:
1.03-1.34), no association was found among participants without the
Cdx 2 VDR risk allele genotype (CC genotype). Our results suggest
that serum vitamin D may play an important role in the early stages
of eGFR decline in adults from the general population. This
association may vary with common genetic differences in the VDR
gene.
Table of Contents
TABLE OF CONTENTS CHAPTER 1 General introduction 1.A Vitamin D
1.A.1 Sources of vitamin D and first steps in vitamin D synthesis
1.A.2 Genomic and non genomic vitamin D functions 1.A.3 VitaminD
receptor (VDR) 1.A.4 Calcium-related actions of vitamin D 1.A.5 Non
calcium-related actions of vitamin D 1.A.6 Vitamin D status 1.A.7
Vitamin D deficiency 1.A.8 Major factor influencing vitamin D
levels 1.B Chronic kidney disease 1.B.1 Definition of chronic
kidney disease 1.B.2 Etiologies of chronic kidney disease 1.B.3
Health consequences of chronic kidney disease 1.B.4 Prevalence,
time trends, and risk of chronic kidney disease References for
chapter 1 CHAPTER 2 Project-specific study aims and literature
review 2.A Literature review related to project 1 2.A.1 Prevalence
of vitamin D deficiency 2.A.2 Prevalence of vitamin D deficiency in
Switzerland 2.A.3 Prevalence and determinants of vitamin D
deficiency in the chronic kidney disease population 2.B Literature
review related to project 2 2.B.1 Vitamin D and kidney function
2.B.2 Vitamin D and blood pressure (epidemiological studies) 2.C
Literature review related to project 3 2.C.1 VDR variants and
end-stage renal disease or chronic kidney disease 2.C.2 VDR
variants and albuminuria 2.C.3 VDR variants, vitamin
supplementation, and kidney function 2.C.4 VDR and chronic kidney
disease major risk factors 45 2.C.5 VDR-vitamin D interaction 47
References for chapter 2 CHAPTER 3 PROJECT 1 Abstract Introduction
Methods Results Discussion Conclusions References for chapter 3
CHAPTER 4 PROJECT 2 Abstract Introduction Methods Results
Discussion Conclusions References for chapter 4 Supplementary
material CHAPTER 5 PROJECT 3 Abstract Introduction Methods Results
Discussion Conclusions References for chapter 5 Supplementary
material CHAPTER 6 General discussion References for chapter 6
APPENDIX Collinearity and backward change in estimate elimination
approach LIST OF TABLES AND FIGURES CHAPTER 1 Figure 1 Sources of
vitamin D and first steps in vitamin D synthesis Figure 2 Genomic
structure of the VDR locus on chromosome 12q13 and position of some
polymorphisms in the vitamin D receptor gene Figure 3 Possible
mechanisms of associations between vitamin D and chronic kidney
disease Table 1 Examples of vitamin D status definitions Table 2
Chronic kidney disease, definition Table 3 Chronic kidney disease,
stages Table 4 Chronic kidney disease, risk factors CHAPTER 2
Figure 1 Adjusted means of 25(OH)D by periods of the year (Panel
A), speaking region (Panel B), and body mass index category (Panel
C) Figure 2 Distributions of 25(OH)D by speaking region and body
mass index category Figure 3 Outline of renoprotective and blood
pressure regulation mechanisms of vitamin D Table 1 Some
associations between VDR polymorphisms and disease or traits
related to kidney function CHAPTER 3 PROJECT 1 Table 1
Characteristics of the SSS participants, by chronic kidney disease
(CKD) status (N=1145) Figure 1 Vitamin D levels and chronic kidney
disease (CKD), unadjusted (Panel A), fully adjusted* (Panel B), and
restricted to participants without vitamin D supplements or therapy
(Panel C) Table 2 Raw numbers and weighted prevalences of
sufficient (>=30 ng/ml), insufficient (20-29.9 ng/ml), and
deficient (<20 ng/ml) vitamin D status, by chronic kidney
disease (CKD) status (N=1145) Table 3 Adjusted a priori interaction
tests of characteristics with transformed 25(OH)D levels using
linear regression, chunck test, and backward elimination procedures
(step 1 to 6), N=1145 Table 4 P values for interaction of selected
attributes with CKD status and stages on vitamin D levels and
month-specific tertiles (models 3 to 6) CHAPTER 4 PROJECT 2 Table 1
Baseline Characteristics of the CoLaus participants, by vitamin D
status (N=4474) Table 2 Kidney phenotypes and outcomes, by vitamin
D status (N=4474) Table 3 Associations of baseline 25(OH)D level
with annual change in eGFR, rapid loss in eGFR, and incident CKD
Table S1 Multivariate association of vitamin D status at baseline
with annual change in estimated GFR (N=4474), Full and reduced
Models Table S2 Multivariate association (Correlated binary
logistic regression) of vitamin D level at baseline with CKD status
at baseline and at follow-up (N=4474), Full and reduced Models
Table S3 Difference in Annual Change in estimated GFR
(ml/min/1.73m2) (95%CI), by vitamin D month-specific quintiles
Table S4 Risk of rapid decline in eGFR, Risk Odds Ratio (95%CI), by
vitamin D month-specific quintiles 120 Table S5 Risk of CKD, Risk
Odds Ratio (95%CI), by vitamin D month-specific quintiles CHAPTER 5
Table 1 Baseline Characteristics of the CoLaus participants, by
vitamin D status (N=3954) Table 2 Adjusted association of 25(OH)D
month-specific quintiles with annual change in estimated GFR, by
Cdx2 VDR genotype Table 3 Adjusted association of 25(OH)D
month-specific quintiles with the risk of rapid decline in
estimated GFR, the risk of chronic kidney disease (CKD), and the
risk of rapid decline in estimated GFR or CKD, by Cdx2 VDR
genotypes (rs11568820) Table 4 Adjusted association of 25(OH)D
month-specific quintiles with the risk of chronic kidney disease
(CKD), and the risk of rapid decline in estimated GFR or CKD, by
Cdx2 VDR genotypes rs11568820) Table S1 Candidate polymorphisms
pair-wise correlations, R2 Table S2 Association between candidate
variants considered separately and mean annual change in eGFR Table
S3 Association between candidate variants and vitamin D phenotypes
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