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