Control of Secondary Hyperparathyroidism by Vitamin D Receptor Agonists in Chronic Kidney Disease

CKD, SHPT, and Vitamin D Deficiency

An estimated 16 million people in the United States have stage 3 or 4 CKD (eGFR 15–59 ml/min per 1.73 m²), with diabetes mellitus and hypertension as major underlying causes (14). Despite the high prevalence of CKD in the adult population, less than 20% of patients who have moderately decreased kidney function are aware of this impairment (15). A prospective, observational study of 1814 CKD patients with a recent historic eGFR of <60 ml/min per 1.73 m² confirmed that 78% of patients had stage 3, 4, or 5 CKD with elevated PTH and significantly reduced 1,25-D levels (16). Rising PTH levels were inversely correlated with declining 1,25-D and 25-D levels; 1,25-D levels were approaching very low levels (<25 pg/ml) as eGFR measurements signified stage 3 CKD. eGFR continued to decline thereafter. These and other study findings substantiate a high incidence of SHPT and low endogenous vitamin D (25-D and/or 1,25-D) levels in CKD patients, supporting the KDIGO recommendations for early and continued measurement of these parameters throughout disease progression (2,9,16–19). These observations support the view that SHPT occurs early and, if left untreated, worsens over time. VDR agonist therapy for dialysis patients has been well documented; however, treatment options for patients with early stages of CKD are less established.

Vitamin D Deficiency and Treatment to Modulate SHPT in CKD Patients

There is ongoing debate regarding a clear definition for what is considered vitamin D (25-D and/or 1,25-D) deficiency. Vitamin 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). Vitamin D concentrations between 32 and 80 ng/mL (200 nmol/L) are generally considered sufficient (2). Vitamin D (25-D and/or 1,25-D) sufficiency is less well defined because numerous factors contribute to achieving adequate endogenous vitamin D levels, and the nomenclature for endogenous and exogenous vitamin D is very similar (Table 1). Because 1,25-D functions as a native hormone, providing complex, tissue-specific signaling throughout the body, it is a challenge to accurately measure the relative contribution of exogenously administered vitamin D with signaling that is occurring through autocrine/paracrine feedback loops (20). The interrelated effects between native and supplemented vitamin D are reiterated in a study examining the effects of exogenously administered 1,25D (i.e., calcitriol) in healthy volunteers and uremic patients. Gallieni et al. (21) showed that although dialysis patients have impaired uptake and metabolism of 25-D, treatment with calcitriol not only repleted serum 1,25-D levels but also increased the uptake of 25-D (as examined in monocytes). Thus, with exogenous 1,25-D administration, there are potential complementary benefits to both 1,25-D and 25-D in an effort to rebalance the hormonal system.

Treatment of Vitamin D Deficiency and SHPT in Patients with Stages 3 and 4 CKD

Deficiencies in 25-D and/or 1,25-D have been associated with an elevated risk of cardiovascular disease and mortality in the general population (22,23). Suboptimal levels of vitamin D contribute to the development of SHPT through reduced intestinal Ca absorption, increased PTH production, and parathyroid cell proliferation (24). Elevated PTH may also initiate increased Ca and P resorption from bone and promote vascular calcification (24,25). Despite elevation in PTH and reductions in endogenous vitamin D (i.e., 25-D and 1,25-D), serum Ca and P usually remain within normal physiologic range in stages 3 and 4 CKD (16,17).

Inactive forms of supplementary vitamin D, ergocalciferol (vitamin D₂), and cholecalciferol (vitamin D₃), significantly increase 25-D and 1,25-D levels in patients with stages 3 and 4 CKD and suppress, but do not normalize, PTH concentrations (26–28). Beginning with stage 4 CKD, the ability of vitamin D supplements to correct elevated PTH concentrations is significantly reduced compared with earlier stages of CKD (26,28). 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 osteomalacia due to vitamin D deficiency and possibly have other benefits.

The biologically active VDR agonists calcitriol and paricalcitol, and the prohormone doxercalciferol, suppress PTH in a dose-related fashion independent of the stage of CKD. Placebo-controlled trials of these exogenously administered agents in patients with stages 3 and 4 CKD demonstrated that calcitriol and doxercalciferol elevated serum Ca, although doxercalciferol may have been less calcemic than calcitriol (3,29,30). Trials of paricalcitol showed significant and sustained control of PTH, with minimal alterations in Ca and P compared with placebo (30). Although the changes observed in Ca and P in these studies are consistent with animal data showing differences in the calcemic and phosphatemic effects of these agents (31,32), definitive claims of differences between compounds await randomized trials comparing these agents in patients with CKD stages 3 and 4. Markers of bone formation, such as bone-specific alkaline phosphatase, were also significantly reduced by VDR agonist treatment (3,29,30). Current KDIGO guidelines do not recommend bone mineral density measurements for CKD but do suggest that stages 3 to 5 CKD patients be measured for serum PTH or bone-specific alkaline phosphatase to predict for low or high bone turnover (2).

Treatment of SHPT in Dialysis Patients

In the late 1980s, intravenous (IV) calcitriol was recommended as an alternative therapy to either oral calcitriol or parathyroidectomy in dialysis patients with SHPT. Long-term intermittent infusions of IV calcitriol 1 to 2.5 μg thrice weekly for an average of 11.5 months in dialysis patients with concomitant osteitis fibrosa achieved significant reductions in PTH and alkaline phosphatase, and resulted in fewer episodes of hypercalcemia than experienced with prior therapy (33). In the late 1990s, investigators demonstrated that by lowering the level of PTH in hemodialysis patients, IV calcitriol 2 μg twice weekly not only attenuated the SHPT effects but also displayed cardioprotective effects (34). Interestingly, 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 (35).

Doxercalciferol (a prohormone that can be hepatically activated into a VDR agonist) was originally investigated as a treatment for osteoporosis (36) and later demonstrated its efficacy by reducing PTH in hemodialysis patients, albeit with elevations in serum Ca and P (37,38). Unfortunately, there have been no studies directly comparing doxercalciferol with other VDR agonists. Alphacalcidol (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 (39). Vitamin-resistant disorders, such as renal bone disease, hypoparathyroidism, and pseudodeficiency rickets, which usually require large amounts of vitamin D, respond to physiologic doses of alphacalcidol. Alphacalcidol may cause hypercalcemia. In a randomized prospective phase III study, IV paricalcitol 0.04 to 0.24 μg (given for up to 32 weeks) showed similar or improved PTH suppression and fewer hypercalcemic episodes compared with IV calcitriol 0.01 to 0.06 μg (40).

Optimal PTH Suppression through Individualized Dosing and Continuous VDR Agonist Therapy

In 2003, KDOQI experts offered CKD stage-specific PTH target ranges; these targets lacked rigorous trial evidence and are no longer considered adequate for management of the individual patient (1). Bone biopsy series in dialysis patients indicate a high prevalence of adynamic bone (low bone turnover) despite PTH levels in or above the KDOQI recommended range, and this is thought to be due to overly aggressive treatment of SHPT in many patients (41). Black dialysis patients in particular may require maintenance of a higher PTH level to avoid adynamic bone (42). Although a patient may not reach PTH levels within KDOQI ranges, continued use of VDR agonists usually leads to significantly reduced PTH that remains stable over time and is accompanied by normalization of other markers of high bone turnover, such as bone-specific alkaline phosphatase and osteocalcin (30,43,44). In the clinical setting, the optimal level of PTH suppression by VDR agonists has been a matter of discussion because PTH levels are lowered and steady themselves at varying levels on the basis of individual patient response to therapy. Hypercalcemia after VDR agonist therapy may be an indication of ensuing adynamic bone and also suggests that the dose of VDR agonist should be reduced (45). In the recently released KDIGO guidelines, target ranges for PTH are set in context with the upper limit of normal per the PTH assay used (2). However, the guidelines do not make formal recommendations for PTH levels in CKD patients. Ideally, an optimal PTH level would result in a nearly normal bone formation rate (BFR). Unfortunately, PTH has only a weak correlation with BFR; therefore, despite achieving otherwise “normal” PTH levels, individuals may have low, normal, or high BFR. In general, patients with CKD stages 3 to 5 who are not on dialysis should achieve stable PTH levels near the upper limit of normal that are maintained with VDR agonist therapy while avoiding hypercalcemia and hyperphosphatemia. In dialysis patients, PTH levels should, in general, be stable and maintained at two or more times the upper limit of normal with VDR agonist therapy while avoiding hypercalcemia. The KDIGO guidelines suggest a PTH goal of two to nine times the upper limit for the assay being used in patients with CKD stage 5D (2). An elevated alkaline phosphatase level is suggestive of inadequately suppressed PTH, and therapy should be intensified to further suppress PTH.

Similar to treating other hormone-deficient diseases (e.g., hypothyroidism) (46), it is the authors' opinion that VDR agonist treatment should in general be continuous in dialysis patients so that patients can maintain normal to nearly normal levels of vitamin D hormone rather than being treated for episodic vitamin D deficiencies and/or rising PTH levels. These patients show moderate to severe 1,25-D deficiency (8) in addition to commonly having hyperphosphatemia and relative or absolute hypocalcemia. The hormonal and mineral imbalances (i.e., 1,25-D, Ca, and P) are potent inducers for PTH secretion and parathyroid proliferation. Uninterrupted use of VDR agonists can therefore remove the PTH stimulatory effect of 1,25-D deficiency and help maintain normal serum Ca, although greater use of phosphate binders may be necessary. This rationale is also consistent with the hypothesis that treatment of the 1,25-D hormonal deficiency plays a role in maintaining health via activation of the VDR in multiple organ systems, such as kidney, immunologic, and cardiovascular systems (reviewed by Andress (47)).

PTH Control by VDR Agonists and Survival

Conclusions

Optimal SHPT control is important in managing the course of CKD, as well as reestablishing PTH, mineral, and vitamin D balances in the CKD patient. It is clear that vitamin D deficiency contributes to the development of SHPT in CKD patients. Depending 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 physiologic levels, because signaling pathways are disrupted owing to a reduction in VDR activity. Characteristics and some of the challenges associated with vitamin D therapies for SHPT in CKD patients are presented in Table 3.

Guidelines for the treatment of CKD patients with SHPT were recently updated by the KDIGO working group to include a more recent perspective on SHPT treatment in CKD patients since the prior 2003 guidelines; comprehensive study details are presented by the KDIGO group (1,2). Taking the KDIGO guidance into account, as well as practical patient management experiences, several considerations are proposed to ensure optimal SHPT control in CKD patients, including early recognition of reduced eGFR, evaluation of PTH, 25-D, and/or 1,25-D starting at stage 3 CKD; optimizing VDR agonist dosing per PTH response in the individual patient; maintenance of continuous VDR agonist therapy to ensure continued PTH suppression; and vigilant monitoring of Ca and P to conform with target ranges (Table 2). The authors believe that it is a rational approach to maintain continuous VDR agonist therapy; however, there are no data to support the effectiveness of interrupted use. In addition to management of SHPT, the overall goals of these proposals are to treat what is actually a chronic hormonal deficiency and increase patient survival. Numerous observational analyses have shown beneficial effects of VDR agonists on both cardiovascular and all-cause mortality rates (8,11,22,56). These potential vitamin D-reliant cardiovascular effects and survival benefits remain to be confirmed in prospectively planned, randomized, controlled trials.