Download Secondary Hyperparathyroidism in CKD: Usefulness of VDR

Secondary Hyperparathyroidism in CKD:
Usefulness of VDR Agonists
Reference: Sprague SM, Coyne D. Control of
secondary hyperparathyroidism by vitamin d
receptor agonists in chronic kidney disease.
Clin J Am Soc Nephrol. 2010;5:512–518.
Introduction: SHPT in CKD
• The last few decades have seen the developments in the treatment of
secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD).
• Consequently, a better understanding of the underlying pathophysiology
and development of advanced and safer medications have resulted.
• Effective treatment options have evolved from surgical removal of the
parathyroid gland to pharmacologic intervention focused on reestablishing
hormonal and mineral balances.
• Besides, earlier recognition of CKD via estimated GFR and educational
efforts have led to advancements in diagnosis and treatment of elevated
parathyroid hormone (PTH) and vitamin D defi ciency.
• Vitamin D [25-hydroxyvitamin D (25-D) and/or 1,25-dihydroxyvitamin D
(1,25-D)] deficiency is usually defined as concentrations <10 ng/mL (25
nmol/L), whereas vitamin D insufficiency is defined as levels between 10
and 32 ng/mL (80 nmol/L).
• Generally, sufficient vitamin D concentrations are in between 32 and 80
ng/mL (200 nmol/L).
• Low vitamin D (25-D and 1,25-D) levels are associated with CKD
progression as well as increased risk of mortality beginning at stage
3 CKD.
• Observational studies report that the use of oral or injectable
vitamin D and/or vitamin D receptor (VDR) agonists like calcitriol in
patients on dialysis or with stages 3 and 4 CKD has been correlated
with enhanced survival.
• Clinical studies support the efficacy and safety of VDR agonists as
effective treatments for SHPT.
• These agents effectively treat SHPT and vitamin D deficiency,
however dosing needs to be optimized for each patient since
patients respond in an individualized manner to treatment to
suppress and stabilize PTH levels.
• On the basis of results from clinical studies and through the
practical use of therapies to control elevated PTH, a number of
considerations have arisen when using VDR agonists that should be
taken into account for providing optimal SHPT control in patients
with CKD (see Table 1).
Treatment of Vitamin D Defi ciency
and SHPT: CKD Stages 3 and 4
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•
Although inactive forms of supplementary vitamin D, ergocalciferol (vitamin D2),
and cholecalciferol (vitamin D3), signifi cantly increase 25-D and 1,25-D levels in
patients with stages 3 and 4 CKD, and suppress PTH, they do not normalize PTH
concentrations. Starting with stage 4 CKD, the ability of vitamin D supplements to
correct elevated PTH concentrations is signifi cantly reduced compared with earlier
stages of CKD. These supplements are generally considered ineffective for PTH
suppression in usual doses in patients with stage 5 CKD (before or in those
receiving dialysis), although they may prevent steomalacia due to vitamin D defi
ciency and possibly have other benefi ts.
Calcitriol and paricalcitol are the biologically active VDR agonists, while the
doxercalciferol is a prohormone. These agents suppress PTH in a dose-related
fashion independent of the stage of CKD. These exogenously administered agents
demonstrated elevated serum Ca, although doxercalciferol may have been less
calcemic than calcitriol in patients with stages 3 and 4 CKD. Compared with
placebo, paricalcitol showed signifi cant and sustained control of PTH, with
minimal alterations in Ca and P.
Treatment of SHPT in Dialysis Patients
• An alternative therapy to either oral calcitriol or parathyroidectomy
is intravenous (I.V.) calcitriol in dialysis patients with SHPT. However,
the increased use of calcitriol as a therapeutic intervention has
been associated with a reduction in parathyroidectomy rates in the
late 1990s to <1% and a shift in the treatment paradigm from a
surgical intervention to pharmacologic management of SHPT.
• Alpha-calcidol, which is not approved for use in the United States, is
1α-hydroyvitamin D3, which is rapidly converted in the liver to 1,25dihydroxy vitamin D3. Vitamin resistant disorders, such as renal
bone disease, hypoparathyroidism, and pseudodefi ciency rickets,
usually require large amounts of vitamin D. These disorders respond
to physiologic doses of alphacalcidol, though it may cause
hypercalcemia. Compared with I.V. calcitriol 0.01–0.06 μg I.V.,
paricalcitol 0.04–0.24 μg (given for up to 32 weeks) showed similar
or improved PTH suppression and fewer hypercalcemic episodes in
a randomized prospective phase III study.
PTH Control by VDR Agonists and
Survival
Effects of Vitamin D Receptor Agonist Treatment on
Survival in Dialysis Patients
• Improved survival after VDR agonist therapy has been
reported by numerous observational studies in dialysis
patients.
• Patients with elevated mineral levels outside of KDOQIbased normal ranges had increased risks of allcause
mortality.
• A significantly increased risk of death was associated with
hypercalcemia, hyperphosphatemia, and increased Ca×P.
• Likewise, even abnormally low mineral levels elevated a
patient’s risk of death, rounding out a U-shaped effect on
mortality.
PTH Control by VDR Agonists and
Survival
Effects of VDR Agonist Treatment on Survival in
Patients with Stages 3 and 4 CKD
• Recent observational studies have explored the relationship
between the use of VDR agonists with survival in CKD
stages 3 and 4 patients.
• The findings from these studies have reported that the use
of oral VDR agonist is associated with signifi cantly better
survival and a lower risk of initiating dialysis compared with
those not prescribed treatment.
• The addition of vitamin D therapy, as anticipated,
suppressed PTH, while episodes of hypercalcemia and/ or
hyperphosphatemia were more frequent in calcitriol
recipients.
Conclusions
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•
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Optimal SHPT control has a vital role in managing the course of CKD, as well as
reestablishing PTH, mineral
and vitamin D balances in these patients.
Undoubtedly, vitamin D defi ciency is responsible for the development of SHPT in
CKD patients.
Based on the stage of kidney dysfunction, repletion of both inactive (25-D) and
active (1,25-D) vitamin D may be needed to adequately replace and balance
physio-logic levels, because signaling pathways are disrupted owing to a reduction
in VDR activity.
Table 2 outlines the characteristics and some of the challenges that are associated
with vitamin D therapies for SHPT in CKD patients.
Maintaining a continuous VDR agonist therapy in CKD patients is considered
rational; besides, there are no data to support the effectiveness of interrupted use.
The overall goals of these proposals in addition to the management of SHPT are to
treat the chronic hormonal deficiency, thereby increasing patient survival.
The beneficial effects of VDR agonists on both cardiovascular and allcause
mortality rates have been testified by numerous observational analyses.
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