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  1. 1. 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
  2. 2. Vitamin D 3 25-Hydroxyvitamin D 3 25(OH)D HO OH OH HO OH HO Vitamin Hormone 1,25-Dihydroxyvitamin D 3 1,25(OH) 2 D 3 or Calcitriol 1 α OH VDR
  3. 3. Slatopolsky et al. Kidney International 61 (s80) s143-s148. 2003
  4. 5. 1α Hydroxlase Deficiency <ul><li>Enzyme that converts 25D > 1,25D </li></ul><ul><li>Regulated by a number of factors </li></ul><ul><ul><li>e.g. Phosphorus, FGF23, Uremia, Acidosis </li></ul></ul><ul><li>1α OH KO results in severe bone and immune related impairments </li></ul>
  5. 6. Tissue Distribution of the Vitamin D Receptor System Tissue Gastrointestinal Esophagus, stomach, small intestine, large intestine, colon Hepatic Liver parenchyma cells Renal Proximal and distal tubules, collecting duct Endocrine Parathyroid, pancreatic  -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
  6. 7. Zasloff Nat Med 2006, Liu et al, Science 2006
  7. 8. Vitamin D is bad… <ul><li>Animal models, high doses of active vitamin D leads to vessel calcification </li></ul><ul><ul><li>Niederhoffer N et al, J Vasc Res 1997 </li></ul></ul><ul><ul><li>Fleckenstein-Grun G et al, J Cardiovasc Pharmacol 1995 </li></ul></ul><ul><ul><li>Kingma JG et al, Artery 1988 </li></ul></ul>
  8. 9. Team <ul><li>Ming Teng, MD </li></ul><ul><li>Myles Wolf, MD, MMSc </li></ul><ul><li>Norma Ofsthun, PhD </li></ul><ul><li>Edmund Lowrie, MD </li></ul><ul><li>Michael Lazarus, MD </li></ul>Hypotheses: Survival difference between those treated with Paricalcitol compared to those treated with Calcitriol
  9. 10. Analysis of Survival According to Type of Vitamin D Therapy Teng et al. N Engl J Med . 2003;349:446-456. Paricalcitol Calcitriol Survival (%) 0 5 10 15 20 25 30 35 40 Survival (%) Switch to Calcitriol 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) 0 10 20 30 40 50 60 70 80 90 100 0 10 20 30 40 50 60 70 80 90 100 0 5 10 15 20 25 30 35 40
  10. 11. Where is Vitamin D acting? Minerals and PTH D-receptor Activation in Endothelial cells, Myocytes, etc…
  11. 12. t=0 No D D 100% 0% time Starting D is time dependent…
  12. 13. D No D t=365 t=90 t=0 t=180 D No D D No D D 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
  13. 14. Marginal Structural Models: Time Dependent Confounding by Indication but… <ul><li>Hypothesis: IV Vit D is associated with survival </li></ul>Mortality IV Vit D <ul><li>These determine whether or not to give IV vitamin D </li></ul>Ca, PO 4 , PTH <ul><li>Baseline Ca, P, PTH is associated with survival </li></ul><ul><li>These changes may be associated with survival </li></ul>Ca, PO 4 , PTH <ul><li>IV vitamin D changes these values </li></ul><ul><li>These changes determine whether to continue IV vitamin D </li></ul>
  14. 15. Hazard Ratio Risk of Death on D Versus no D Teng et al. J Am Soc Nephrol. 2005;16:1115-1125. *Adjusted for monthly Ca, P, PTH before & after initiation of treatment Among the first dialysis studies to adjust for covariates at multiple time points
  15. 16. Baseline Characteristics* <ul><li>D No D </li></ul><ul><li>Age (yrs) 61 63 </li></ul><ul><li>Diabetes (%) 53 52 </li></ul><ul><li>Calcium (mg/dl) 8.6 8.7 </li></ul><ul><li>Phosphorus (mg/dl) 5.3 5.3 </li></ul><ul><li>Ca X P (product) 46 46 </li></ul><ul><li>Intact PTH (pg/ml) 354 179 </li></ul>*Differences in AV access, Race, and other variables
  16. 17. 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 14.6 13.8 7.6 0 5 10 15 20 25 30 35 Mortality CVD Mortality 2-Year Mortality Rate Deaths/100 Person-Years No IV Vitamin D IV Vitamin D
  17. 18. <ul><li>K/DOQI </li></ul><ul><li>When to stop D: </li></ul><ul><li>If Ca > 10.2 </li></ul><ul><li>If P > 6.0 </li></ul><ul><li>If PTH < 150 </li></ul>
  18. 19. <ul><li>PO4 >6.4 mg/dl (quintile 5) HR 0.75 , 95% CI 0.64-0.83 </li></ul><ul><li>Ca >9.1 mg/dl (quintile 5) HR 0.72 , 95% CI 0.64-0.81 </li></ul><ul><li>Ca X P >55 HR 0.71 , 95% CI 0.63-0.80 </li></ul><ul><li>PTH <96.7 pg/ml (quintile 1) HR 0.78 , 95% CI 0.71-0.87 </li></ul>
  19. 20. Phosphorus at start of Dialysis and 2 year Mortality
  20. 21. PTH at start of Dialysis and 2 year Mortality
  21. 22. Limitations <ul><li>Historical cohort study </li></ul><ul><ul><li>Prospective collection of data </li></ul></ul><ul><ul><li>Comparison of contemporaneous groups </li></ul></ul><ul><ul><li>All inclusive of patients on injectable D </li></ul></ul><ul><ul><li>Accuracy of Exposures and Outcomes </li></ul></ul><ul><ul><li>No retrospective abstraction of new data </li></ul></ul><ul><ul><li>Study reflected “real world” practice </li></ul></ul><ul><ul><li>Nonetheless, these findings remain observational and </li></ul></ul><ul><ul><li>require verification by additional studies including </li></ul></ul><ul><ul><li>RCT’s and studies formulated upon strong biological </li></ul></ul><ul><ul><li>mechanisms… </li></ul></ul>
  22. 23. Dialysis Units Throughout the U.S. DATA Blood Spectra FMC-NA Proton MGH ARMORR Liquid Nitrogen Relational Database Molecular Testing
  23. 24. ArMORR - A ccelerated M ortality O n R enal R eplacement <ul><li>Prospective observational study of 10,018 incident hemodialysis patients with demographic and laboratory data available as well as remnant blood samples </li></ul><ul><li>Will be used to test a variety of hypotheses including those suggested here </li></ul>
  24. 25. Conclusions <ul><li>Vitamin D has effects well beyond mineral metabolism, including effects on the cardiovascular system </li></ul><ul><li>Vitamin D may be linked with a survival advantage in ESRD patients – observational and ne </li></ul><ul><li>Many other studies…..animal and human, must be done </li></ul>Disclosures of Support - Work presented herein have been supported by the National Institutes of Health and Abbott Laboratories