Geoffrey Block MD Director of Clinical Research Denver Nephrologists

1. Vitamin D metabolism in the pathogenesis of renal osteodystrophy and secondary hyperparathyroidism Geoffrey Block MD Director of Clinical Research Denver Nephrologists Assistant Clinical Professor of Medicine University of Colorado Health Sciences Center Denver, CO Kevin Martin MB BCh Professor of Internal Medicine Director, Division of Nephrology Saint Louis University Health Sciences Center Saint Louis, MO

2. Vitamin D and hyperparathyroidism • Vitamin D plays an important role in hyperparathyroidism • Use of vitamin D metabolites widespread in patients on dialysis • Potential toxicity of the active metabolites of vitamin D • Use vitamin D analogs instead • Potential use of vitamin D in earlier stages of kidney disease • Hyperparathyroidism starts very early in the course of kidney disease Kevin Martin MB BCh

3. Calcitriol production • The active metabolite of vitamin D, calcitriol, is synthesized in the kidney • Process depends on: • Glomerular filtration • Uptake of 25-OH vitamin D by the proximal tubule • Delivery to the 1-hydroxylase enzyme in the mitochondria by binding of the precursor to megalin Kevin Martin MB BCh

4. Proteinuria, diabetes, and vitamin D deficiency • Are patients with proteinuria of modest degree and/or diabetes more susceptible to 25-OH vitamin D deficiency and early development of secondary hyperparathyroidism as a results of their disturbed protein loss in the urine? Gonzalez EA, Martin KJ et al. Am J Nephrol. 2004;24:503-510. Geoffrey Block MD

5. Proteinuria and vitamin D deficiency • Increased vitamin D deficiency in patients with proteinuria • Continued loss of vitamin D-binding protein with the bound substrate in the urine • Patients with chronic kidney disease are prone to vitamin D deficiency Kevin Martin MB BCh

6. Diabetes and vitamin D deficiency • Proteinuria-induced deficiency • Other factors seem to be at work in diabetes: • Diabetics tend not to have severe hyperparathyroidism in general • Perhaps related to poor glucose control etc… Kevin Martin MB BCh

7. Non-PTH mediated survival effects of vitamin D • Publication by Drs Thadhani and Teng • Survival advantage of injectable vitamin D in patients with CKD stage 5 on dialysis • Potential non-PTH-mediated survival effects of vitamin D • CV mortality rate of people with stage 3 and 4 are increased to levels that cannot be explained by traditional CV risk factors • Must investigate vitamin D deficiency earlier in stages 3 and 4 Teng M, Thadhani R, et al. N Engl J Med. 2003; 349:446-456 Teng M, Thadhani R, et al. J Am Soc Nephrol. 2005; 16:1115-1125 Geoffrey Block MD

8. Non-PTH mediated survival effects of vitamin D • Data derived from a retrospective study of patients: hypothesis-generating • Intriguing observation with potential biological and clinical significance • Additional research required Kevin Martin MB BCh

9. Careful analysis • Cautious about making broad generalizations of these results • What is clear is that patients who never get vitamin D appear to be different • If one is to accept the survival benefits with large amounts of injectable vitamin D then question is: • Whether it should be used in all patients or not Geoffrey Block MD Kevin Martin MB BCh

10. Vitamin D and bone turnover • Patients without severe hyperparathyroidism should not receive large doses of injectable vitamin D: • Adynamic bone is a risk factor for other types of cardiovascular disease “Should we give large doses of vitamin D in the presence of adynamic bone for a presumed survival benefit and ignore the potential increase in mortality from furthering vascular calcification?” Kevin Martin MB BCh

11. Population differences • Recent publication by Dr Young: • Analysis using the DOPPS database looking at effect of mineral metabolism on outcome • In a prevalent population, we’re not able to see the same profound effect of vitamin D administration as Drs Teng and Thadhani observed “Population differences play a role in this result” Young EW, Akiba T, et al. Am J Kidney Dis. 2004; 44:34-38 Geoffrey Block MD

12. “I prefer moderation” • Give vitamin D when appropriate without inducing what is overtly oversuppressed parathyroid hormone • Avoiding high calcium and high phosphorus with or without vitamin D is a required objective Geoffrey Block MD

13. Oral vs. injectable vitamin D • In the DOPS cohort there’s a lot of oral administration of vitamin D vs injectable use: • What is the difference? • What are the postadministration effects? • Are analogs different from calcitriol? • Are all analogs alike? • Can analogs substitute for the active sterols at other tissue sites? Kevin Martin MB BCh

14. Extrarenal effects of vitamin D • Hard to measure in vivo • Seem to relate to cell differentiation and gene regulation Can we exploit the effect of vitamin D in these tissues in favor of a survival benefit? Kevin Martin MB BCh

15. Nutritional vitamin D components instead of pharmacological therapy • Supplements of native vitamin D were given to raise levels of the 25-OH form to above 30 ng/mL • Sometimes it requires large amounts in this patient population • We were limited in terms of demonstrating any clinical effects • May be confounded by the fact that a lot of these patients are also receiving active sterols Gonzalez EA, Martin KJ et al. Am J Nephrol. 2004;24:503-510. Kevin Martin MB BCh

16. Nutritional vitamin D components instead of pharmacological therapy • Measuring extrarenal effects or “extracalcemic” effects of vitamin D sterols is very difficult • Replaced by vitamin D2 (ergocalciferol): only available preparation to be given at a reasonably high dose of 50 000 units once a week or once every second week “With careful study we may see a reduction in the requirement for active sterols but we have not seen that at the moment.” Gonzalez EA, Martin KJ et al. Am J Nephrol. 2004;24:503-510. Kevin Martin MB BCh

17. Additional questions • Do those relative deficiencies change in winter vs summer? • Do the patients’ requirements for 25-OH vitamin D change with the season? • What are the effects of 25-OH vitamin D repletion in patients who are not receiving large doses of active sterols? Geoffrey Block MD Kevin Martin MB BCh

18. Substituting with ergocalciferol • Similar results with stage 3 and 4 with regards to replacing 25-OH vitamin D with ergocalciferol • You showed a relationship between 25-OH vitamin D and PTH in stages 3 and 4 of CKD • Replacing with ergocalciferol often is insufficient to achieve K/DOQI targets for parathyroid hormone Geoffrey Block MD

19. Differential responses • In some patients, correcting the 25-OH D deficiency brings PTH levels down to target, whereas in other patients it is not sufficient • Kidney disease may get so advanced that, although the precursor has been replenished, the remaining kidney tissue can’t produce enough of the active sterol Kevin Martin MB BCh

20. Differential responses • Must categorize the patients: • Diabetics and nondiabetics • Glomerular diseases vs interstitial disease • Rational approach to treatment rather than give every patient everything Kevin Martin MB BCh

21. Concluding remarks “We’ll evolve towards a broader role of vitamin D beyond hyperparathyroidism” “Hopefully it will translate into something meaningful in terms of patient outcome” Geoffrey Block MD Kevin Martin MB BCh