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 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 1,25- 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 0.01–0.06 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 KDOQI- based 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 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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