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VITAMINA D: QUANTO DI NUOVO E DI
IGNOTO?
Mario Cozzolino, MD, PhD
Dipartimento di Scienze della Salute
Università degli Studi di Milano
UO Nefrologia e Dialisi, AO San Paolo, Milano
2
OUTLINE
Basics and background on vitamin D metabolism in CKD Vitamin D deficiency and cardiovascular diseases and its risk factors Natural vitamin D treatment in CKD Perspectives & Conclusions
3
OUTLINE
Basics and background on vitamin D metabolism in CKD Vitamin D deficiency and cardiovascular diseases and its risk factors Natural vitamin D treatment in CKD Perspectives & Conclusions
PTH
Calcio
Fosforo Vitamina
D
FGF23
CKD-MBD
PTH
Calcio
Fosforo Vitamina
D
FGF23
CKD-MBD
TOP 10 Medical Breakthroughs 2007
Adapted from Time Magazine, US Edition 2007 (Dec 24);26:170
Benefits of Vitamin D
• Bone strength
• Diabetes
• Gum disease
• Multiple sclerosis
• Cancer (in particular colon cancer)
7
Vitamin D
Vitamin D metabolism
Vitamin D sources
Nutrition UV-B induced vitamin D
production in the skin
80-90% 10-20%
8
Vitamin D metabolism
Pilz S, et al. Nature Reviews Cardiology 2009, 6: 621-630
Pathophysiology
ng/ml
HL~1 month
pg/ml
HL<1 day
Serum 1,25(OH)2D: Derived from the kidney
Tissue 1,25(OH)2D: Produced from serum 25(OH)D
9
"The Survival advantage conferred by light skin as our ancestors
migrated to higher latitudes is generally believed to have resulted from
the importance of maintaining adequate vitamin D levels under
conditions of reduced exposure to UV-B"
Giovannucci E, Therapy 2008; 5:655-658
Vitamin D and skin
10
Vitamin D (25[OH]D) status in CKD
>30 ng/mL 10-30 ng/mL <10 ng/mL
Decrease in intestinal
calcium absorption and
an increase in PTH in
patients with 25(OH)D
levels < 30ng/mL
(<75nmol/L)
11
Reduced 25D/1,25D Occurs Early in CKD
Levin A, et al. Kidney Int 2007;71:31–8
†p<0.001
iPTH (pg/mL) 1,25D (pg/mL) 25D (ng/mL)
*as measured by 1,25D
n=61 n=117 n=230 n=396 n=355 n=358 n=204 n=93
†
79–70 69–60 59–50 49–40 39–30 29–20 <20
eGFR Interval (mL/min/1.73 m2)
0
≥80
5
10
15
20
25
30
35
40
45
50
1,2
5D
(p
g/m
L)
25
D (
ng
/mL
)
†
0
50
100
150
iPT
H l
eve
l (p
g/m
L)
(n=1814)
12
OUTLINE
Basics and background on vitamin D metabolism in CKD Vitamin D deficiency and cardiovascular diseases and its risk factors Natural vitamin D treatment in CKD Perspectives & Conclusions
Hypothesis: Mechanisms of VDR Activation Impact on CV Outcomes
↓ Atherosclerosis
and vascular
calcification
Li YC, et al. J Clin Invest 2002;110:229–38; Mathieu C, et al. Trends Mol Med 2002;8:174–9
VDR activation
↓ Inflammation
↓ Heart failure
↓ Morbidity and mortality
↓ RAAS
↓ LVH
↑ Cardiomyocyte
remodeling
System Tissue
Gastrointestinal Esophagus, stomach, small intestine, large intestine,
Hepatic Liver parenchyma cells
Endocrine Parathyroid, pancreatic β-cells, thyroid C-cells
Exocrine Parotid gland, sebaceous gland
Reproductive Testis, spermatocytes, ovary, placenta, uterus, endometrium, yolk sac
Immune Thymus, bone marrow, B cells, T cells
Respiratory Lung alveolar cells
Skeletal Osteoblasts, osteocytes, chondrocytes
Muscle Striated muscle
Epidermis/appendage Skin, breast, hair follicles
Central nervous system Brain neurons
Connective tissue Fibroblasts, stroma
VDR Distribution in the Body
Cardiovascular Vascular smooth muscle cells, endothelial cells, cardiomyocytes
Renal Proximal and distal tubules, collecting duct, podocytes
Endothelial cells have VDR
and express 1-alpha hydroxylase Merke, et al. JCI 1989
VSMC cells have VDR
Kawashima H. BBRC. 1987
and express 1-alpha hydroxylase Somjen D, Circulation 2005
Vitamin D and the vasculature
Lack of VDR induces senescence in VSMCs
Absence of VDR in mouse VSMC induces an arrest in G1 phase and a decrease in proliferation levels, probably due to a development of a premature cellular senescence
Valcheva P, et al. Nephrol Dial Transplant 2008;1(Suppl 2):132. #SP313
Growth curve of VSMC in
10% FBS DMEM
100000
200000
300000
400000
500000
0 0 10 20 30 40 50 60
KO y=108924e0.0154x
R2=0.9486
WT y=87445e0.0322x
R2=0.9362
Cell
num
be
r
Time (hours)
WT KO
17
Vitamin D and the cardiovascular system
Vitamin D receptor (VDR) expression:
Heart: Cardiomyocytes and cardiac fibroblasts
Cells of the vessel wall: Endothelial cells,
vascular smoorth muscle cells, macrophages
1-alpha hydroxylase expression:
Heart: Cardiomyocytes and cardiac fibroblasts
Cells of the vessel wall: Endothelial cells,
vascular smooth muscle cells, macrophages
18
Vitamin D receptor (VDR) knock-out mice
Myocardial hypertrophy
Arterial hypertension
Overexpression of renin (renin angiotensin aldosterone system; RAAS)
Xiang W, et al. Am J Physiol Endocrinol Metab 2005;288:125-132
VDR Knock-out models
19
Vitamin D receptor KO
Bouillon R et al. Endocrine Reviews 2008; 29:726-776
Selective VDR knock out in the heart
causes myocardial dysfunction
Gardner DG, et al. 14th Workshop of vitamin D, Brugge, Belgium, Oct 2009
21
Vitamin D effects on the cardiovascular system
VITAMIN D EFFECTS ON THE CARDIOVASCULAR
SYSTEM
EFFECTS ON THE MYOCARDIUM
Antihypertrophic effects
Modulation of calcium flux and contractility
Renin suppression
Modulation of extracellular matrix turnover
EFFECTS ON THE VESSELS
Anti-atherosclerotic effects
Inhibition of vascular calcification
Improvement of endothelial function
EFFECTS ON CARDIOVASCULAR
RISK FACTORS
Reno-protective effects
Anti-hypertensive effects
Anti-diabetic effects
PTH suppression
Anti-inflammatory effects
Anti-oxidative effects
All-cause and CV Mortality in 25D Quartiles
Su
rviv
al
Time (years)
0.6
0.7
0.8
0.9
1
0 2 4 6 8
Q4
(high)
Q3
Q2
Q1
(low)
0.6
0.7
0.8
0.9
1
0 2 4 6 8
Q4
(high)
Q3
Q2
Q1
(low)
All-cause mortality (HR 2.08 [95% CI, 1.60–2.70]
high vs low)
Cardiovascular mortality (HR 2.22 [95% CI, 1.57–3.13]
high vs low)
p<0.001 across all quartiles
Dobnig H, et al. Arch Intern Med 2008;168:1340–9
0
0.5
1
1.5
2
2.5
3
Low Serum 25D Levels (Quartiles) are Associated with Higher Prevalence of Peripheral Arterial Disease
Melamed M et al. Arterioscler Thromb Vasc Biol 2008;28:1179–85
1
(lowest,
<17.8)
2
(17.8 to 23.4)
3
(23.5 to 29.1)
4
(highest,
≥29.2)
Serum 25D, ng/mL
(range)
Pre
vale
nce r
atio
*p<0.001 compared with the reference group of 25D 29.2 ng/mL
REF
*
Multivariable adjusted† prevalence ratios of peripheral arterial disease (PAD)
(ankle/brachial index <0.9) by quartiles of serum 25D
†see notes page for all confounders
• A nested case-control study in 18,225 men (40 to 75 years; no CVD) in the Health Professionals Follow-up Study
Low 25D Levels Associated with Increased Risk of Myocardial Infarction in Men
15.1–22.5 22.6–29.9
0.0
0.5
1.0
1.5
2.0
≤15.0
Rela
tive r
isk o
f M
I o
ver
10 y
ears
≥30.0 REF
Baseline plasma 25D, ng/mL†
2.5
Giovannucci E, et al. Arch Intern Med 2008;168:1174–80
63/87*
*Cases/controls, no; †SI conversion factor: To convert 25D to nanomoles per liter, multiply by 2.496
156/307* 165/299*
70/207*
p-value (trend) <0.01
25
OUTLINE
Basics and background on vitamin D metabolism in CKD Vitamin D deficiency and cardiovascular diseases and its risk factors Natural vitamin D treatment in CKD Perspectives & Conclusions
26
Vitamin D in CKD
Pilz S, et al. Nature Reviews Cardiology 2009, 6: 621-630
Low serum levels of
1,25(OH)2D
Low serum levels of
25(OH)D
Natural (nutritional)
vitamin D treatment
Pathophysiology
Active vitamin D treatment:
1,25(OH)2D (=calcitriol)
or
Selective VDR agonists (ie
paricalcitol, doxercalciferol,
maxacalcitol, falecalcitriol )
27
PTH effects on the cardiovascular system
PTH receptors are widely expressed
throughout the cardiovascular system
including the myocardium
PTH infusions increase blood pressure in
healthy volunteers and PTH modifies
contractile functions of the myocardium
PTH levels were highlighted as a
cardiovascular risk factor in
epidemiological studies
Schlüter KD et al. Cardiovasc Res 1998,37:34-41
Fitzpatrick LA et al. Curr Osteoporos Rep 2008,6:77-83
Hagström E et al. Circulation 2009,119:2765-2771
28
Natural vitamin D effects on PTH
Cozzolino M, et al. Eur J Heart Failure 2010
Impact of VDR activators on CV endpoints and patient outcome
Kidney fibrosis VDR effect
• Interstitial volume • Glomerulosclerosis • TGF-β1
ANF, atrial natriuretic factor; ANP, atrial natriuretic protein; BMP-2, bone morphogenetic protein-2; BNP, brain natriuretic protein; IL-1β,
interleukin-1β; LV, left ventricular; MGP, matrix Gla protein; PAI-1, plasminogen activator inhibitor-1; TGF-β, tumour growth factor-β; TNF-α, tumour necrosis factor-α; VEGF, vascular endothelial growth factor
VDR activators Cardiovascular Modulation Outcome
Inactive vitamin D
• Ergocalciferol
• Cholecalciferol
1α-hydroxyvitamin D
• Alfacalcidol
• Doxercalciferol
1,25-dihydroxyvitamin D
• Calcitriol
Selective 1,25D
• Paricalcitol
• Maxacalcitol
Hormone
Heart
Vasculature
Kidney
VDR
VDR
VDR
VDR
Immune cells VDR
Decreased • Hypertension • Heart weight • LV hypertrophy • Posterior wall thickness • Left ventricular end-
diastolic pressure • BNP, ANF, ANP • Renin and angiotensin • VEGF • PAI-1 • Tissue factor
Increased • Fractional shortening • Vascular relaxation • Thrombomodulin
Acute Repair
Integrity restored
Chronic Repair
Damage limitation
Morbidity/
Mortality
Improved
Calcification VDR effect
Inducers • BMP-2 • Type 1 collagen • IL-1β and TNF-α
Inhibitors • MGP • Osteopontin • Type IV collagen
Other effects
Cozzolino M, et al. Eur J Heart Failure 2010
Impact of VDR activators on CV endpoints and patient outcome
Kidney fibrosis VDR effect
• Interstitial volume • Glomerulosclerosis • TGF-β1
ANF, atrial natriuretic factor; ANP, atrial natriuretic protein; BMP-2, bone morphogenetic protein-2; BNP, brain natriuretic protein; IL-1β,
interleukin-1β; LV, left ventricular; MGP, matrix Gla protein; PAI-1, plasminogen activator inhibitor-1; TGF-β, tumour growth factor-β; TNF-α, tumour necrosis factor-α; VEGF, vascular endothelial growth factor
VDR activators Cardiovascular Modulation Outcome
Inactive vitamin D
• Ergocalciferol
• Cholecalciferol
1α-hydroxyvitamin D
• Alfacalcidol
• Doxercalciferol
1,25-dihydroxyvitamin D
• Calcitriol
Selective 1,25D
• Paricalcitol
• Maxacalcitol
Hormone
Heart
Vasculature
Kidney
VDR
VDR
VDR
VDR
Immune cells VDR
Decreased • Hypertension • Heart weight • LV hypertrophy • Posterior wall thickness • Left ventricular end-
diastolic pressure • BNP, ANF, ANP • Renin and angiotensin • VEGF • PAI-1 • Tissue factor
Increased • Fractional shortening • Vascular relaxation • Thrombomodulin
Acute Repair
Integrity restored
Chronic Repair
Damage limitation
Morbidity/
Mortality
Improved
Calcification VDR effect
Inducers • BMP-2 • Type 1 collagen • IL-1β and TNF-α
Inhibitors • MGP • Osteopontin • Type IV collagen
Other effects
VDR activators
Inactive vitamin D
•Ergocalciferol
•Cholecalciferol
1α-hydroxyvitamin D
•Alfacalcidol
•Doxercalciferol
1,25-dihydroxyvitamin D
•Calcitriol
Selective 1,25D
•Paricalcitol
•Maxacalcitol
Cozzolino M, et al. Eur J Heart Failure 2010
Impact of VDR activators on CV endpoints and patient outcome
Kidney fibrosis VDR effect
• Interstitial volume • Glomerulosclerosis • TGF-β1
ANF, atrial natriuretic factor; ANP, atrial natriuretic protein; BMP-2, bone morphogenetic protein-2; BNP, brain natriuretic protein; IL-1β,
interleukin-1β; LV, left ventricular; MGP, matrix Gla protein; PAI-1, plasminogen activator inhibitor-1; TGF-β, tumour growth factor-β; TNF-α, tumour necrosis factor-α; VEGF, vascular endothelial growth factor
VDR activators Cardiovascular Modulation Outcome
Inactive vitamin D
• Ergocalciferol
• Cholecalciferol
1α-hydroxyvitamin D
• Alfacalcidol
• Doxercalciferol
1,25-dihydroxyvitamin D
• Calcitriol
Selective 1,25D
• Paricalcitol
• Maxacalcitol
Hormone
Heart
Vasculature
Kidney
VDR
VDR
VDR
VDR
Immune cells VDR
Decreased • Hypertension • Heart weight • LV hypertrophy • Posterior wall thickness • Left ventricular end-
diastolic pressure • BNP, ANF, ANP • Renin and angiotensin • VEGF • PAI-1 • Tissue factor
Increased • Fractional shortening • Vascular relaxation • Thrombomodulin
Acute Repair
Integrity restored
Chronic Repair
Damage limitation
Morbidity/
Mortality
Improved
Calcification VDR effect
Inducers • BMP-2 • Type 1 collagen • IL-1β and TNF-α
Inhibitors • MGP • Osteopontin • Type IV collagen
Other effects
Cardiovascular
Hormone
Heart
Vasculature
Kidney
VDR
VDR
VDR
VDR
Immune cells VDR
Cozzolino M, et al. Eur J Heart Failure 2010
Impact of VDR activators on CV endpoints and patient outcome
Kidney fibrosis VDR effect
• Interstitial volume • Glomerulosclerosis • TGF-β1
ANF, atrial natriuretic factor; ANP, atrial natriuretic protein; BMP-2, bone morphogenetic protein-2; BNP, brain natriuretic protein; IL-1β,
interleukin-1β; LV, left ventricular; MGP, matrix Gla protein; PAI-1, plasminogen activator inhibitor-1; TGF-β, tumour growth factor-β; TNF-α, tumour necrosis factor-α; VEGF, vascular endothelial growth factor
VDR activators Cardiovascular Modulation Outcome
Inactive vitamin D
• Ergocalciferol
• Cholecalciferol
1α-hydroxyvitamin D
• Alfacalcidol
• Doxercalciferol
1,25-dihydroxyvitamin D
• Calcitriol
Selective 1,25D
• Paricalcitol
• Maxacalcitol
Hormone
Heart
Vasculature
Kidney
VDR
VDR
VDR
VDR
Immune cells VDR
Decreased • Hypertension • Heart weight • LV hypertrophy • Posterior wall thickness • Left ventricular end-
diastolic pressure • BNP, ANF, ANP • Renin and angiotensin • VEGF • PAI-1 • Tissue factor
Increased • Fractional shortening • Vascular relaxation • Thrombomodulin
Acute Repair
Integrity restored
Chronic Repair
Damage limitation
Morbidity/
Mortality
Improved
Calcification VDR effect
Inducers • BMP-2 • Type 1 collagen • IL-1β and TNF-α
Inhibitors • MGP • Osteopontin • Type IV collagen
Other effects
Modulation
Decreased •Hypertension •Heart weight •LV hypertrophy •Posterior wall thickness •Left ventricular end-diastolic pressure •BNP, ANF, ANP •Renin and angiotensin •VEGF •PAI-1 •Tissue factor
Increased •Fractional shortening •Vascular relaxation •Thrombomodulin
Cozzolino M, et al. Eur J Heart Failure 2010
Impact of VDR activators on CV endpoints and patient outcome
Kidney fibrosis VDR effect
• Interstitial volume • Glomerulosclerosis • TGF-β1
ANF, atrial natriuretic factor; ANP, atrial natriuretic protein; BMP-2, bone morphogenetic protein-2; BNP, brain natriuretic protein; IL-1β,
interleukin-1β; LV, left ventricular; MGP, matrix Gla protein; PAI-1, plasminogen activator inhibitor-1; TGF-β, tumour growth factor-β; TNF-α, tumour necrosis factor-α; VEGF, vascular endothelial growth factor
VDR activators Cardiovascular Modulation
Inactive vitamin D
• Ergocalciferol
• Cholecalciferol
1α-hydroxyvitamin D
• Alfacalcidol
• Doxercalciferol
1,25-dihydroxyvitamin D
• Calcitriol
Selective 1,25D
• Paricalcitol
• Maxacalcitol
Hormone
Heart
Vasculature
Kidney
VDR
VDR
VDR
VDR
Immune cells VDR
Decreased • Hypertension • Heart weight • LV hypertrophy • Posterior wall thickness • Left ventricular end-
diastolic pressure • BNP, ANF, ANP • Renin and angiotensin • VEGF • PAI-1 • Tissue factor
Increased • Fractional shortening • Vascular relaxation • Thrombomodulin
Outcome
Acute Repair
Integrity restored
Chronic Repair
Damage limitation
Morbidity/
Mortality
Improved
Calcification VDR effect
Inducers • BMP-2 • Type 1 collagen • IL-1β and TNF-α
Inhibitors • MGP • Osteopontin • Type IV collagen
Other effects
Outcome
Acute Repair
Integrity restored
Chronic Repair
Damage limitation
Morbidity/
Mortality
Improved
Vitamin D and Outcome: Classical U-Curve Relationship
Adverse events
Vitamin D status
Immune system
Cancer defense
Bone health
sHPT
RAS
Myoc. fibrosis
Mortality
Survival benefit in ESRD (Teng / Thadani etc.)
Accelerated arteriosclerosis
low high ultra- high
Mortality
Ca x P
intermediate
Cozzolino M & Branderburg V, Clinical Nephrology 2009,
0
1
2
3
4
5
6
7
5 10 15 20 25 30 35 40
-2
0
2
4
6
8
10
5 10 15 20 25 30 35
-2
0
2
4
6
8
10
0.40 0.60 0.80 1.00 1.20 1.40 1.60
0
1
2
3
4
5
6
7
0.40 0.60 0.80 1.00 1.20 1.40 1.60
4
6
8
10
12
14
16
18
20
0.40 0.60 0.80 1.00 1.20 1.40 1.60
1,25D and 25D Levels are Correlated with Arterial Parameters in HD Patients
London G, et al. J Am Soc Nephrol 2007;18:613–20
Log10 25D (μg/L)
1,25D (ng/L)
r= -0.535
p<0.0001
n=52
r=0.616
p<0.0001
n=42
r=0.584
p<0.001
n=37
FM
D (
% o
f b
ase
line
dia
me
ter)
Ao
rtic
PW
V (
m/s
)
Bra
ch
ial a
rtery
dis
ten
sib
ility
(kP
a1
0-1
.10
-3)
FM
D (
% o
f b
ase
line
dia
me
ter)
4
6
8
10
12
14
16
18
20
5 10 15 20 25 30 35 40
Ao
rtic
PW
V (
m/s
)
r= -0.616
p<0.0001
n=40
r=0.632
p<0.001
n=30
r=0.741
p<0.0001
n=27
Bra
ch
ial a
rtery
dis
ten
sib
ility
(kP
a1
0-1
.10
-3)
Flow-mediated dilation (FMD) Brachial artery distensibility Aortic PWV
37
Vitamin D status and sudden cardiac death
in hemodialysis patients
38
Kaplan Meier curve for sudden cardiac death according to 25-hydroxyvitamin D groups
Vitamin D status and
CVD mortality
Pilz S, et al. Nephrology, Dialysis and Transplantation, 2011 Mar 4. [Epub ahead of print]
Patients with eGFR <60 mL/min/1.73m² (n=444)
During a median follow up of 9.4 years 159 CVD deaths occurred
25(OH)D levels
>30 ng/ml
20-29.99 ng/ml
10-19.99 ng/ml
<10 ng/ml
Adjusted HR: Severe deficient vs.
sufficient 5.61 (1.89-16.6)
128 CKD 2-5 Patients
41
OUTLINE
Basics and background on vitamin D metabolism in CKD Vitamin D deficiency and cardiovascular diseases and its risk factors Natural vitamin D treatment in CKD Perspectives & Conclusions
March 23, 2011
43
Vitamin D supplementation
and mortality
Autier P, et al. Arch Intern Med 2007; 167: 1730-1737
44
Take home messages
The cardiovascular system is a target tissue for vitamin D
and a poor vitamin D status, which is present in the majority
of CKD patients, is a risk factor for cardiovascular mortality
It is suggested to test for and treat reduced 25(OH)D
concentrations with natural vitamin D: this therapy is safe,
cheap and simple, reduces PTH levels and might also reduce
cardiovascular events and mortality
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