Secondary Hyperparathyroidism in CKD: Usefulness of VDR Agonists

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Secondary Hyperparathyroidism in CKDUsefulness
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. 20105512518.

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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 lt10 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).

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• 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).

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Treatment of Vitamin D Defi ciency and SHPT CKD
Stages 3 and 4

• 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.

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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 lt1 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 1a-hydroyvitamin D3, which
  is rapidly converted in the liver to
  1,25-dihydroxy 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
  0.010.06 µg I.V., paricalcitol 0.040.24 µg
  (given for up to 32 weeks) showed similar or
  improved PTH suppression and fewer hypercalcemic
  episodes in a randomized prospective phase III
  study.

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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
  KDOQI-based normal ranges had increased risks of
  allcause mortality.
• A significantly increased risk of death was
  associated with hypercalcemia, hyperphosphatemia,
  and increased CaP.
• Likewise, even abnormally low mineral levels
  elevated a patients risk of death, rounding out
  a U-shaped effect on mortality.

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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.

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Conclusions

• 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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Comprehensive Basketin Anemia Management