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Vitamin D and ESRD Survival
Ravi Thadhani, MD, MPHAssociate Professor of Medicine
Harvard Medical School
Director of Clinical Research in Nephrology
Massachusetts General Hospital
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Vitamin D3 25-Hydroxyvitamin D3
25(OH)D
HO
OH
OHHO
OH
HO
Vitamin Hormone
1,25-Dihydroxyvitamin D3
1,25(OH)2D3 or Calcitriol1αOH
VDR
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Slatopolsky et al. Kidney International 61 (s80)
s143-s148. 2003
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1α Hydroxlase Deficiency
- Enzyme that converts 25D > 1,25D
- Regulated by a number of factors- e.g. Phosphorus, FGF23, Uremia, Acidosis
- 1α OH KO results in severe bone and immune related impairments
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System Tissue
Gastrointestinal Esophagus, stomach, small intestine, large intestine, colon
Hepatic Liver parenchyma cells
Renal Proximal and distal tubules, collecting duct
Endocrine Parathyroid, pancreatic β-cells, thyroid C-cells
Exocrine Parotid gland, sebaceous gland
Reproductive Testis, ovary, placenta, uterus, endometrium, yolk sac,
Immune Thymus, bone marrow, B cells, T cells
Respiratory Lung alveolar cells
Musculoskeletal Osteoblasts, osteocytes, chondrocytes, striated muscle
Epidermis/appendage Skin, breast, hair follicles
Central nervous system Brain neurons
Connective tissue Fibroblasts, stroma
Cardiovascular Smooth Muscle and endothelial cells, myocytes
Tissue Distribution of the Vitamin D Receptor
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Zasloff Nat Med 2006, Liu et al, Science 2006
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Vitamin D is bad…
• Animal models, high doses of active vitamin D leads to vessel calcification
– Niederhoffer N et al, J Vasc Res 1997– Fleckenstein-Grun G et al, J Cardiovasc Pharmacol 1995– Kingma JG et al, Artery 1988
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Team
Ming Teng, MDMyles Wolf, MD, MMSc
Norma Ofsthun, PhDEdmund Lowrie, MDMichael Lazarus, MD
Hypotheses: Survival difference between those treated with Paricalcitol compared to
those treated with Calcitriol
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Teng et al. N Engl J Med. 2003;349:446-456.
Paricalcitol
Calcitriol
Su
rviv
al (
%)
0
10
20
3040
50
60
70
80
90
100
0 5 10 15 20 25 30 35 40
Su
rviv
al (
%)
Switchto Calcitriol
0
10
20
30
40
50
60
70
80
90100
0 5 10 15 20 25 30 35 40
Switch to Paricalcitol
3-year survival:59% vs 51%
Log rank P<0.001
2-year survival:73% vs 64%
Log rank P = 0.04
N = 67,399 N = 16,483
Follow-Up (mo)
Analysis of Survival According to Type of Vitamin D Therapy
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D-receptor Activation in Endothelial cells,Myocytes, etc…
Where is Vitamin D acting?
Minerals and PTH
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t=0
No D
D
100%
0%
time
Starting D is time dependent…
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D
No D
t=365t=90t=0 t=180
D
No DD
No DD
No D
HR=0.67
HR=0.75
HR=0.73
HR=0.80
Time dependent analyses examining 2-year survival starting at different time points
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Marginal Structural Models: Time Dependent Confounding by Indication
but… Hypothesis: IV Vit D is associated with survival
MortalityIV Vit D
• These determine whether or not to give IV vitamin D
Ca, PO4, PTH
• Baseline Ca, P, PTH is associated with survival
• These changes may be associated with survival
Ca, PO4, PTH
• IV vitamin D changes these values
• These changes determine whether to continue IV vitamin D
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0.48
0.80
0.74
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
Crude Time-Dependent Cox Marginal Structural*
Ha
zard
Ra
tio
Ris
k of
De
ath
on
D V
ers
us n
o D
Teng et al. J Am Soc Nephrol. 2005;16:1115-1125.
*Adjusted for monthly Ca, P, PTH before & after initiation of treatmentAmong the first dialysis studies to adjust for covariates at multiple time points
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Baseline Characteristics*
D No DAge (yrs) 61 63Diabetes (%) 53 52Calcium (mg/dl) 8.6 8.7Phosphorus (mg/dl) 5.3 5.3Ca X P (product) 46 46Intact PTH(pg/ml) 354 179
*Differences in AV access, Race, and other variables
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Active Vitamin D Therapy and Survival in Patients on Hemodialysis
Teng et al. J Am Soc Nephrol. 2005;16:1115-1125.
P<0.001
28.6
14.613.8
7.6
0
5
10
15
20
25
30
35
Mortality CVD Mortality
2-Y
ear
Mo
rtal
ity
Rat
e D
eath
s/10
0 P
erso
n-Y
ears
No IV Vitamin D IV Vitamin D
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Characteristic Deaths N %Age (years)
< 50 607 6445 950-60 701 5271 1360-70 1285 7456 1770-80 1666 5670 29
>80 761 1946 39Race
Caucasian 3267 16723 20African American 1483 10562 14
Other 270 1930 14Calcium (mg/dl)
< 8.4 1384 6817 208.4-8.7 921 5295 178.7-9.0 902 5546 169.0-9.5 1006 6554 15
>9.5 807 5003 16Phosphate (mg/dl)
<4.5 1194 5811 214.45-5.2 1054 6221 175.2-5.9 915 5655 165.9-6.9 900 5888 15
>6.9 957 5640 17PTH (quintiles)
<47.2 1170 5894 2047.2-100.5 1078 5818 19
100.5-172.2 995 5903 17172.2-309.7 957 5799 17
>309.7 820 5846 14
0.9 1.00.8
K/DOQI
When to stop D:
-If Ca > 10.2
-If P > 6.0
-If PTH < 150
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• PO4 >6.4 mg/dl (quintile 5) HR 0.75, 95% CI 0.64-0.83
• Ca >9.1 mg/dl (quintile 5) HR 0.72, 95% CI 0.64-0.81
• Ca X P >55 HR 0.71, 95% CI 0.63-0.80
• PTH <96.7 pg/ml (quintile 1) HR 0.78, 95% CI 0.71-0.87
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Phosphorus at start of Dialysis and 2 year Mortality
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PTH at start of Dialysis and 2 year Mortality
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Limitations• Historical cohort study
– Prospective collection of data– Comparison of contemporaneous groups– All inclusive of patients on injectable D– Accuracy of Exposures and Outcomes – No retrospective abstraction of new data – Study reflected “real world” practice
Nonetheless, these findings remain observational andrequire verification by additional studies including RCT’s and studies formulated upon strong biological mechanisms…
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Dialysis Units Throughout the U.S.
DATA
Blood
Spectra MGH
Liquid Nitrogen
Relational Database
Molecular Testing
FMC-NAProton
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ArMORR - Accelerated Mortality On Renal Replacement
• Prospective observational study of 10,018 incident hemodialysis patients with demographic and laboratory data available as well as remnant blood samples
• Will be used to test a variety of hypotheses including those suggested here
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Conclusions• Vitamin D has effects well beyond mineral
metabolism, including effects on the cardiovascular system
• Vitamin D may be linked with a survival advantage in ESRD patients – observational and ne
• Many other studies…..animal and human, must be done
Disclosures of Support - Work presented herein have been supported by the National Institutes of Health and Abbott Laboratories