View the PowerPoint presentation in your browser
25
Vitamin D and ESRD Survival Ravi Thadhani, MD, MPH Associate Professor of Medicine Harvard Medical School Director of Clinical Research in Nephrology Massachusetts General Hospital
Transcript of View the PowerPoint presentation in your browser
Vitamin D and ESRD Survival
Ravi Thadhani, MD, MPHAssociate Professor of Medicine
Harvard Medical School
Director of Clinical Research in Nephrology
Massachusetts General Hospital
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
Slatopolsky et al. Kidney International 61 (s80)
s143-s148. 2003
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
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
Zasloff Nat Med 2006, Liu et al, Science 2006
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
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
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
D-receptor Activation in Endothelial cells,Myocytes, etc…
Where is Vitamin D acting?
Minerals and PTH
t=0
No D
D
100%
0%
time
Starting D is time dependent…
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
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
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
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
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
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
• 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
Phosphorus at start of Dialysis and 2 year Mortality
PTH at start of Dialysis and 2 year Mortality
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…
Dialysis Units Throughout the U.S.
DATA
Blood
Spectra MGH
Liquid Nitrogen
Relational Database
Molecular Testing
FMC-NAProton
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
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
