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