Brenner and Rector's The Kidney, 8th ed.

CHAPTER 56. Vitamin D, Calcimimetics, and Phosphate-Binders^[*]

William G. Goodman L. Darryl Quarles

		Key Disturbances in Calcium, Phosphorus, and Vitamin D Metabolism in Chronic Kidney Disease, 1904
		Overview of Clinical Management, 1904
		Therapeutic Goals, 1905
		Vitamin D, 1906
		Normal Metabolism, 1906
		Mechanisms of Action, 1907
		Impact of Chronic Kidney Disease on Vitamin D Metabolism, 1907
		Consequences of Impaired Renal Calcitriol Synthesis in Chronic Kidney Disease, 1907
		Extrarenal Calcitriol Synthesis, 1908
		Vitamin D Nutrition, 1909
		Therapeutic Use of Vitamin D Sterols in Chronic Kidney Disease, 1909
		Use of Vitamin D Sterols in Patients with Chronic Kidney Disease Who Do Not Require Dialysis, 1910
		Use of Vitamin D Sterols in Patients with Chronic Kidney Disease Who Require Dialysis, 1912
		Calcimimetic Agents, 1915
		Phamacokinetics and Pharmacodynamics of Cinacalcet, 1915
		Ust of Cinacalcet in Patients Undergoing Dialysis, 1916
		Use of Cinacalcet in Patients with Chronic Kidney Disease Who Do Not Require Dialysis, 1918
		Phosphate-Binding Agents, 1919
		Phosphorus Metabolism in Chronic Kidney Disease, 1919
		Therapeutic Objectives, 1920
		Calcium-Binding Compounds, 1920
		Calcium-Free Compounds, 1921
		Calcium Supplements, 1921
		Management of Bone Disease, Mineral Metabolism, and Parathyroid Gland Function, 1921
		Specific Therapeutic Considerations, 1922
		Chronic Kidney Disease, Stages 2, 3, and 4, 1922
		Chronic Kidney Disease, Stage 5, 1923

Chronic kidney disease (CKD) is associated with a number of important disturbances in mineral metabolism, which include hypocalcemia, hyperphosphatemia, and abnormalities in vitamin D metabolism that result in functional calcitriol deficiency.^[1] Elevated plasma levels of parathyroid hormone (PTH), a key calcium-regulating hormone that also affects renal phosphorus excretion, and fibroblast growth factor 23 (FGF-23), a recently identified phosphorus-regulating hormone, occur often. ^{[2] [3]} The major consequences of disordered mineral metabolism in CKD are secondary hyperparathyroidism (SHPT), metabolic bone disease, and extraskeletal calcification. ^{[1] [4] [5]}The primary focus of the current chapter is to review the therapeutic options for managing these disorders among patients with CKD and to discuss the specific objectives of treatment, including their benefits and risks.

* This work was supported by USPHS grant number DK-61007.
KEY DISTURBANCES IN CALCIUM, PHOSPHORUS, AND VITAMIN D METABOLISM IN CHRONIC KIDNEY DISEASE

A broad overview of the factors that disrupt calcium and phosphorus metabolism and that contribute to alterations in parathyroid gland function and renal bone disease among patients with CKD has been presented elsewhere in this volume (see Chapter 52 ). Details about the physiologic role of the kidney in regulating calcium and phosphorus excretion in the urine have also been provided (see Chapter 16 ). These topics are not addressed further other than to emphasize that calcium and phosphorus metabolism is regulated systemically in a manner that is integrated closely. Some of the adverse effects of CKD on mineral metabolism arise because the capacity of the kidneys to regulate calcium and phosphorus excretion in the urine is diminished. These changes interfere with the maintenance of total body balance for both calcium and phosphorus. Other abnormalities are due to alterations in the metabolic functions of the kidney, particularly as regard the synthesis of calcitriol, or 1,25-dihydroxyvitamin D, the most potent metabolite of vitamin D. ^{[6] [7]}

The regulation of calcium and phosphorus metabolism not only involves the kidneys but also bone, intestine, and the parathyroid glands. Certain factors, such as PTH, calcitriol, and FGF-23, participate in regulating both minerals. Perturbations in calcium metabolism thus often influence phosphorus homeostasis, and changes in phosphorus metabolism commonly affect calcium homeostasis. These interactions have immediate relevance when evaluating various disorders of mineral metabolism among patients with CKD and when formulating therapeutic interventions to manage them.

OVERVIEW OF CLINICAL MANAGEMENT

Essential components of the clinical management of patients with CKD include measures to optimize calcium metabolism, to offset the consequences of abnormal vitamin D metabolism, to minimize phosphorus retention and to prevent hyperphosphatemia, and to control parathyroid gland function as part of a broad effort to maintain skeletal health. ^{[8] [9]} Specific interventions include the use of dietary calcium supplements, phosphate-binding compounds, vitamin D sterols, and calcimimetic agents.^[10] Each has a specific purpose, but all have potentially important consequences with respect to the physiologic regulation of calcium and phosphorus metabolism in persons with impaired renal function.

Several reports have linked disturbances in calcium and phosphorus metabolism to adverse clinical outcomes including cardiovascular disease and death among patients undergoing dialysis regularly. ^{[11] [12]} The mechanisms responsible are not understood fully, but they may involve the process of vascular calcification, which is quite common among patients with CKD.^[5] Some of the abnormalities in mineral metabolism that have been associated with vascular calcification are due to kidney disease per se, whereas others are related to therapeutic interventions designed to modify parathyroid gland function, to manage renal bone disease, and to control serum phosphorus levels among patients undergoing dialysis.^[13] Similar concerns about the relationship between abnormalities in mineral metabolism and cardiovascular disease have been raised among persons with mild to moderate CKD, particularly with regard to disturbances in phosphorus homeostasis. ^{[14] [15]} The safe and effective utilization of any particular therapeutic strategy for managing bone disease, mineral metabolism, and parathyroid gland function among patients with CKD thus requires an understanding not only of its potential benefit but also of the risks involved.

Certain treatments are directed toward specific molecular targets, and their mechanism of action has been defined clearly ( Table 56-1 ). ^{[9] [13]} Vitamin D sterols and calcimimetic agents thus interact with the vitamin D receptor (VDR) and the calcium-sensing receptor (CaSR), respectively, to elicit predictable biologic responses. ^{[9] [13]} Other therapeutic measures such as phosphate-binding agents and oral calcium supplements are less specific, and they affect mineral metabolism more broadly with divergent biologic effects, some of which are adverse (see Table 56-1 ). To a considerable extent, the safety and efficacy of strategies to manage bone disease and mineral metabolism among patients with CKD are determined not only by their therapeutic specificity but also by the frequency and severity of untoward side effects.

TABLE 56-1 -- Therapeutic Interventions for Treating Secondary Hyperparathyroidism and Managing Mineral Metabolism Among Patients with Chronic Kidney Disease

Agent	Target	Benefit	Risk
Cinacalcet HCl	CaSR	Inhibit PTH secretion	Hypocalcemia
		Lower plasma PTH
Vitamin D sterols	VDR	Inhibit PTH synthesis	Hypercalcemia
		Lower plasma PTH	Hyperphosphatemia
			Extraosseous/vascular calcification
Calcium carbonate Calcium acetate	Reduce intestinal PO4 absorption	Control/lower serum PO4	Hypercalcemia Hyperphosphatemia, extraosseous/vascular calcification
Sevelamer HCl	Reduce intestinal PO4 absorption	Control/lower serum PO4	Acidemia
Lanthanum carbonate	Reduce intestinal PO4 absorption	Control/lower serum PO4
Aluminum hydroxide Aluminum carbonate	Reduce intestinal PO4 absorption	Control/lower serum PO4	Aluminum retention/toxicity
Ca2+ supplements	Increase dietary Ca2+ intake	Restore/maintain Ca2+ nutrition	Hypercalcemia

CaSR, calcium-sensing receptor; PTH, parathyroid hormone; VDR, vitamin D receptor.

THERAPEUTIC GOALS

The extent to which calcium, phosphorus, and vitamin D homeostasis is disrupted among patients with CKD differs substantially according to the level of renal functional impairment.^[6] Several aspects of calcium and phosphorus metabolism differ fundamentally among patients with mild to moderate CKD, who have substantial residual renal function, and those with advanced CKD, who have little or no residual renal function and require treatment with dialysis. ^{[16] [17] [18]} Different strategies are required to appropriately address the disparate therapeutic needs of these distinct groups of patients.

The acceptable range for certain biochemical parameters also differs according to the level of renal function as summarized in the guidelines developed by the Kidney/Dialysis Outcomes Quality Initiative (K/DOQI) of the National Kidney Foundation ( Table 56-2 ).^[19] Interventions suitable for patients undergoing dialysis regularly thus may not be inappropriate or may even be contraindicated for persons with less advanced renal failure. The safe and effective clinical management of patients with CKD requires a thorough understanding about how the kidneys participate normally in regulating calcium and phosphorus metabolism and how these regulatory functions become compromised as kidney disease develops and progresses.

TABLE 56-2 -- Recommended Ranges for Selected Biochemical Parameters According to Stage of Chronic Kidney Disease (CKD) as Summarized in the K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in CKD

Recommended Serum Values
CKD Stage	GFR Range (mL/min/1.73 m2)	Phosphorus (mg/dL)	Calcium (corrected) (mg/dL)	Ca × P	Intact PTH (pg/mL)
3	30–59	2.7–4.6	8.4–10.2		35–70
4	15–29	2.7–4.6	8.4–10.2		70–110
5	<15, dialysis	3.5–5.5	8.4–9.5	<55	150–300

Modified from National Kidney Foundation DOQI™ Kidney Disease Outcomes Quality Initiative. Am J Kidney Dis 43:S1–S201, 2004.

Ca, calcium; CKD, chronic kidney disease; GFR, glomerular filtration rate; K/DOQI, Kidney/Dialysis Outcomes Quality Initiative; P, phosphorus; PTH, parathyroid hormone.

VITAMIN D

Normal Metabolism

Vitamin D is a secosteroid that undergoes two important hydroxylation steps that result ultimately in the formation of calcitriol, or 1,25-dihydroxyvitamin D ( Fig. 56-1 ). ^{[20] [21]} Native vitamin D is available in the diet either as cholecalciferol, which is vitamin D₃ from animal sources, or as ergocalciferol, which is vitamin D₂ from plant sources. Vitamin D₃ is also produced endogenously in skin from 7-dehydrocholesterol during exposure to ultraviolet light (see Fig. 56-1 ).^[22] It is then released from subcutaneous tissue into the bloodstream, where it circulates bound to vitamin D-binding protein (DBP). ^{[21] [23]}

FIGURE 56-1 Synthesis and metabolism of vitamin D. See text for additional details. (Reproduced from Dusso AS, Brown AJ, Slatopolsky E: Vitamin D. Am J Physiol Renal Physiol 289:F8–F28, 2005.)

The initial step in the activation of vitamin D occurs in the liver, where the carbon atom at position 25 of the side chain of the molecule undergoes hydroxylation to form 25-hydroxyvitamin D, the predominant circulating metabolite of vitamin D (see Fig. 56-1 ). ^{[21] [24]} This conversion is not regulated tightly, and it is largely substrate-dependent. ^{[21] [24]} Both vitamin D₃ and vitamin D₂ are metabolized through the same hepatic pathway. Measurements of the serum level of 25-hydroxyvitamin D are considered to be the best biochemical index of vitamin D nutrition,^[25] at least in part, because this metabolite provides the substrate for various 25-hydroxyvitamin D-1-alpha-hydroxylase enzymes, including the renal 25-hydroxyvitamin D-1-alpha-hydroxylase, that produce the most potent molecular form of vitamin D, that is, calcitriol.^[26]

In the general population, serum 25-hydroxyvitamin D levels vary substantially during the year. ^{[27] [28] [29]} Values are highest in the summer and lowest in the late months of winter.^[28] The prevalence of marginal vitamin D nutrition and overt vitamin D deficiency is generally greater among persons living at geographic locations far from the equator, where both the duration and intensity of sunlight exposure are less compared with tropical latitudes.^[27]In Europe, regional or cultural differences in diet may alter this relationship.^[24] Nevertheless, such findings highlight the importance of photoactivation in the skin for providing adequate substrate for the hepatic synthesis of 25-hydroxyvitamin D to maintain vitamin D nutrition.^[22] They also indicate that the dietary intake of vitamin D is frequently alone insufficient to sustain serum 25-hydroxyvitamin D levels even among persons living in societies that are developed economically and where foods are often fortified with vitamin D. ^{[25] [27]}

Calcitriol, or 1,25-hydroxyvitamin D, is produced subsequently by hydroxylation of the carbon atom located at position 1 of the A ring of 25-hydroxyvitamin D₃ (see Fig. 56-1 ). ^{[21] [24]} The vitamin D₂ equivalent, 25-hydroxyvitamin D₂, also undergoes the same conversion to form 1, 25-dihydroxyvitamin D₂.^[30] The enzyme responsible is the 25-hydroxyvitamin D-1-alpha-hydroxylase.^[31] In kidney, this metabolic step occurs in the mitochondria of epithelial cells in the proximal nephron after the reabsorption of 25-hydroxyvitamin D together with DBP from tubular fluid by a megalin-dependent mechanism.^[32] Calcitriol is then released into peritubular blood, where it circulates in plasma again bound to DBP.^[33]

As mentioned previously, 1,25-hydroxyvitamin D is the most potent metabolite of vitamin D produced endogenously. ^{[21] [24]} It functions systemically as a calcium-regulating hormone, acting primarily through genomic mechanisms. Key target tissues that participate in the regulation of calcium metabolism and that are affected directly by 1,25-hydroxyvitamin D include kidney, intestine, bone, and para thyroid. The receptor for vitamin D, or VDR, is expressed, however, in many other types of cells. Calcitriol thus serves as an important modifier of gene transcription even in tissues that are not involved directly in maintaining calcium homeostasis.

Mechanisms of Action

Genomic

The classic genomic actions of vitamin D are initiated by the binding of 1,25-dihydroxyvitamin D to its receptor in the cytoplasm of cells expressing the VDR. ^{[21] [34]} The ligand-bound VDR subsequently localizes to the cell nucleus, where it forms a heterodimer with the retinoid X receptor (RXR) ( Fig. 56-2 ). ^{[35] [36] [37]} The VDR-RXR complex then interacts with specific nucleotide sequences, or vitamin D response elements (VDREs), within DNA. The nucleotide pairs that comprise the VDREs of different genes vary slightly, but they all share a common palindromic arrangement.^[38] The aggregation of nuclear regulatory proteins and other transcriptional factors together with the DNA-bound VDR-RXR complex serves to modulate gene transcription and mRNA synthesis (see Fig. 56-2 ). ^{[21] [34] [39]} Vitamin D enhances gene expression in some tissues, whereas it inhibits gene expression in others. For example, calcitriol promotes osteocalcin expression in osteoblasts in bone, whereas it inhibits pre-pro-PTH gene transcription in parathyroid tissue. ^{[40] [41]}

FIGURE 56-2 A model depicting interactions among the heterodimeric vitamin D receptor/retinoid X receptor, a vitamin D response element (VDRE), and nuclear factors that modulate gene expression. (Redrawn with permission from Jurutka PW, Whitfield GK, Hsieh JC, et al: Molecular nature of the vitamin D receptor and its role in regulation of gene expression. Rev Endocr Metab Disord 2:203–216, 2001.)

Nongenomic

In some tissues, vitamin D sterols such as calcitriol exert biologic effects over periods of time that are too short to be explained by genomic mechanisms. A discrete receptor, or membrane-associated protein, that is distinct from the VDR may mediate these rapid nongenomic actions. ^{[42] [43] [44] [45] [46]} The term “transcaltachia” was used originally to describe increases in intestinal calcium transport that occurred within 10 to 15 minutes after adding 1,25-dihydroxyvitamin D to fluid used to perfuse the lumen of the proximal small intestine.^[47] Nongenomic mechanisms are likely to account for such findings, and they may contribute, at least in part, to increases in intestinal calcium absorption in persons ingesting oral doses of vitamin D sterols, including patients with CKD.

Impact of Chronic Kidney Disease on Vitamin D Metabolism

Cross-sectional studies document that the serum levels of 1,25-dihydroxyvitamin D decrease progressively as renal function declines ( Fig. 56-3 ). ^{[6] [7]} Such changes are due largely to reductions in renal calcitriol synthesis, although inadequate vitamin D nutrition may contribute by making less 25-hydroxyvitamin D available for conversion by the renal 25-hydroxyvitamin D-1-alpha-hydroxylase (vide infra). ^{[48] [49]}

FIGURE 56-3 Results from a cross-sectional study indicating that serum 1,25-dihydroxyvitamin D levels decrease on average as renal function declines. (Reproduced from Martinez I, Saracho R, Montenegro J, et al: The importance of dietary calcium and phosphorous in the secondary hyperparathyroidism of patients with early renal failure. Am J Kidney Dis 29:496–502, 1997.)

Serum calcitriol levels vary substantially, however, at any given level of renal function. Values remain normal in some patients with early CKD, but they are reduced markedly in others with the same level of renal functional impairment. Serum calcitriol levels are typically quite low among patients with advanced CKD, but they may be normal or reduced only slightly in some individuals with severely impaired renal function. ^{[48] [49]} Despite such variations, the proportion of patients with low serum calcitriol levels increases as renal function worsens. This biochemical disturbance adversely affects intestinal calcium absorption and thus contributes substantially to modest reductions in serum calcium concentration and to the hypocalciuria that characterizes patients with mild to moderate CKD.^[50] Several mechanisms are involved.

Consequences of Impaired Renal Calcitriol Synthesis in Chronic Kidney Disease

Calcitriol modulates the expression of several key proteins responsible for the transepithelial movement of calcium ions not only in intestine but also in kidney ( Fig. 56-4 ). ^{[51] [52]} The calbindins are vitamin D-dependent proteins that buffer free calcium ions within the cytoplasm of epithelial cells in calcium-transporting epithelia and participate in the translocation of calcium from the apical to the basolateral cell membrane.^[53] Calcitriol together with calcium also modulates the expression of two proteins belonging to the vanilloid family of transient receptor potential (TRP) proteins TRPV-5 and TRPV-6. ^{[54] [55] [56] [57]} Each is a constitutively activated calcium channel that mediates calcium uptake across the apical membrane of renal and intestinal epithelial cells, respectively.^[58] Calcium uptake into cells through the apical membrane represents the rate-limiting step for the transepithelial movement of calcium ions.^[59] A vitamin D-regulatory element that enhances mRNA expression has been identified in the promoter region of both genes. ^{[60] [61]} Decreases in the level of expression of the calbindins, TRPV-5, and TRPV-6 in intestinal epithelial cells thus provide a molecular basis to account for impaired intestinal calcium absorption among patients whose serum calcitriol levels are reduced due to CKD (see Fig. 56-4 ).^[62]

FIGURE 56-4 A schematic drawing to illustrate that the levels of expression of calbindin, and transient receptor potential proteins TRPV-6 and possibly TRPV-5 in intestinal epithelial cells regulate vitamin D-dependent calcium absorption.

Reductions in intestinal calcium absorption can lead to overt hypocalcemia in some patients with mild to moderate CKD who are not receiving oral calcium supplements or vitamin D sterols, a disturbance that not only stimulates PTH secretion directly but also promotes PTH synthesis.^[63] Low serum calcitriol levels also attenuate the inhibitory actions of 1,25-dihydroxyvitamin D on pre-pro-PTH gene transcription, thereby promoting PTH production by parathyroid tissue.^[64] Either alone or together, these biochemical alterations contribute to the development of SHPT among patients with mild to moderate CKD. Indeed, SHPT represents an appropriate physiologic response to circumstances where the amounts of calcium entering extracellular fluid, particularly from the intestine, are diminished, the proximate cause of SHPT in other clinical disorders. These include hypovitaminosis D, overt vitamin D deficiency, prolonged dietary calcium restriction, and genetic disorders, due to inactivating mutations of the renal 25-hydroxyvitamin D-1-alpha-hydroxylase or the VDR. ^{[65] [66] [67] [68] [69] [70]}

Extrarenal Calcitriol Synthesis

The kidneys are recognized generally as a key site of 1,25-hydroxyvitamin D production, and the synthesis of calcitriol in renal tissue is thought to be the primary determinant of the serum level of 1,25-hydroxyvitamin D among persons with normal renal function.^[26] Other tissues, however, also express the 25-hydroxyvitamin D-1-alpha-hydroxylase.^[21] Such findings suggest that 1,25-dihydroxyvitamin D synthesis is regulated in a tissue-specific manner to serve autocrine or paracrine needs.^[71] Adequate vitamin D nutrition is required to support the activity of these tissue-specific enzymes by providing sufficient amounts of the necessary substrate, 25-hydroxyvitamin D, to satisfy local needs for calcitriol production ( Fig. 56-5 ).

FIGURE 56-5 Calcitriol, or 1,25-dihydroxyvitamin D, is synthesized from 25-hydroxyvitamin D in kidney and other tissues that express the 25-hydroxyvitamin D-1-alpha-hydroxylase. The required substrate is 25-hydroxyvitamin D, which is produced in liver from native vitamin D. Polar metabolites of vitamin D that are used commonly as therapeutic agents among patients with chronic kidney disease, stage 5, including calcitriol, paricalcitol, and doxercalciferol are not metabolized to either native vitamin D or 25-hydroxyvitamin D. These compounds thus do not satisfy the classic nutritional requirements for vitamin D.

VITAMIN D NUTRITION

Although assessments of vitamin D nutrition are done regularly in the diagnostic evaluation of persons with normal renal function who have evidence of metabolic bone disease or other disorders of calcium metabolism, they have not been used traditionally for the biochemical assessment and clinical management of patients with CKD. Inadequate vitamin D nutrition or overt vitamin D deficiency is common, however, among those with CKD as judged by measurements of the serum levels of 25-hydroxyvitamin D. ^{[48] [72] [73]} Proteinuria, which results in ongoing losses of DBP together with vitamin D in the urine, increases the likelihood of vitamin D deficiency among patients with CKD. Serum 25-hydroxyvitamin D levels are thus often reduced markedly in those with nephrotic-range proteinuria, particularly among diabetic patients, who often have substantial urinary losses of protein. ^{[48] [72]} Certain guidelines for managing bone disease and mineral metabolism among patients with CKD, such as those assembled by the K/DOQI of the National Kidney Foundation, thus recommend that routine biochemical screening be done to identify persons with CKD who also have evidence of vitamin D insufficiency/deficiency.^[19]

Serum 25-hydroxyvitamin D levels that exceed 30ng/mL are considered to reflect adequate vitamin D nutrition, whereas values below this threshold serve as a biochemical indicator of either vitamin D insufficiency or overt vitamin D deficiency.^[27] Some authorities suggest that the distinction between adequate and inadequate vitamin D nutrition be made using values that are substantially higher to provide greater assurance that inadvertent vitamin D deficiency does not occur.^[74] Nevertheless, treatment with native vitamin D is recommended to restore vitamin D nutrition when the serum levels of 25-hydroxyvitamin D are judged to be supoptimal.^[24] Repeated measurements of serum 25-hydroxyvitamin D levels are done to assess the effectiveness of treatment.

Either ergocalciferol, vitamin D₂, or cholecalciferol, vitamin D₃, can be used to raise serum 25-hydroxyvitamin D levels, but specific guidance for the dosing of ergocalciferol has been provided in the K/DOQI guidelines because this compound is more readily available for use clinically.^[19] Both the frequency of dosing with ergocalciferol and the amounts needed to restore adequate vitamin D nutrition differ according to the biochemical severity of vitamin D deficiency as outlined in the K/DOQI guidelines. Despite these recommendations, definitive information about the efficacy of strategies for treating overt vitamin D deficiency or for correcting inadequate vitamin D nutrition among patients with CKD is not available.

The need for and suitability of maintaining adequate vitamin D nutrition is not considered to differ between patients with CKD and those with normal renal function. In the general population, inadequate vitamin D nutrition can account for reductions in bone mass and for osteoporosis, and it represents a risk factor for hip fracture in older persons. ^{[75] [76]} Moreover, restoring adequate vitamin D nutrition has been reported to substantially diminish the risk of hip fracture in selected high-risk populations.^[77] In this regard, the K/DOQI guidelines offer specific recommendations about assessing vitamin D nutrition among patients with CKD, stages 1 through 4, but not for patients with CKD, stage 5, including those who require treatment with dialysis.^[19] In part, the disparity may be attributable to the fact that many patients undergoing dialysis are regularly given vitamin D sterols, such as calcitriol, paricalcitol, doxercalciferol, or alfacalcidol, to treat SHPT.

A substantial proportion of those managed with dialysis do not, however, have overt SHPT and are not treated routinely with vitamin D sterols.^[18] The nutritional requirements for vitamin D in such patients may thus remain unmet as judged by measurements of the serum levels of 25-hydroxyvitamin D (see Fig. 56-5 ). The therapeutic use of vitamin D sterols that were developed originally and specifically for the treatment of SHPT is unlikely to satisfy this nutritional need. Calcitriol, paricalcitol, doxercalciferol, and alfacalcidol are not metabolized to 25-hydroxyvitamin D, and their use therapeutically does not raise serum 25-hydroxyvitamin D levels. Although definitive information about the prevalence and severity of vitamin D deficiency in the dialysis population is not available, it seems prudent to identify such patients and to correct the disorder when present.

Treatment with native vitamin D, rather than with other vitamin D sterols including calcitriol represents the conventional strategy for correcting vitamin D deficiency in the general population both in adults with osteomalacia and in children with rickets.^[65] The same considerations apply to patients with CKD. The approach thus acknowledges lingering uncertainties about whether calcitriol alone fully satisfies the biologic and metabolic requirements for vitamin D in all tissues.^[24] It is also based upon the principle that providing adequate amounts of native vitamin D allows endogenous metabolic pathways to generate any and all of the necessary molecular forms of vitamin D required by specific target tissues. Maintaining normal serum levels of 25-hydroxyvitamin D satisfies the substrate requirements of various extrarenal 25-hydroxyvitamin D-1-alpha-hydroxylases that are involved in the local, tissue-specific regulation of calcitriol synthesis. More polar metabolites of vitamin D such as calcitriol, paricalcitol, doxercalciferol and alfacalcidol do not serve as substrates for these enzymes (see Fig. 56-5 ).

THERAPEUTIC USE OF VITAMIN D STEROLS IN CHRONIC KIDNEY DISEASE

SHPT is common among patients with CKD. ^{[78] [79]} It develops early during the clinical course of CKD, progresses in sever-ity as kidney function declines, and is characterized by persistent elevations in plasma PTH levels that lead to metabolic bone disease and to other important disturbances in calcium and phosphorus metabolism.^[80] To control SHPT medically, therapeutic measures designed specifically to lower plasma PTH levels are required. Until the introduction of calcimimetic agents, vitamin D sterols represented the only definitive pharmacologic intervention for the disorder.^[8] Strategies for managing SHPT with vitamin D sterols differ substantially, however, between patients with mild to moderate CKD, who have significant residual renal function, and those managed with dialysis, whose residual renal function is negligible or absent.

Use of Vitamin D Sterols in Patients with Chronic Kidney Disease Who Do Not Require Dialysis

Histologic evidence of bone disease, particularly hyperparathyroidism, is common among patients with mild to moderate CKD, even in those with only modestly elevated plasma PTH levels.^[81] Treatment with vitamin D is recommended to lower plasma PTH levels among patients with CKD, stages 3 and 4, when values exceed 70pg/mL and 110pg/mL, respectively, as measured by conventional immunoradiometric assays (IMAs).^[19] Such assays are known to detect not only the full-length peptide hormone composed of 84 amino acids, or PTH(1-84), but also one or more amino terminally truncated peptide fragments of PTH including PTH(7-84). ^{[82] [83]} Vitamin D therapy should be undertaken, however, only when the serum levels of calcium and phosphorus are controlled adequately to limit the risks of hypercalcemia and hyperphosphatemia, disturbances that not only can adversely affect renal function but also aggravate soft tissue and vascular calcification. ^{[5] [19]}

Patients with SHPT due to mild to moderate renal insufficiency who are not receiving oral calcium supplements or vitamin D sterols often have serum calcium levels that fall within the lower range of normal. Some have overt hypocalcemia.^[84] Reductions in vitamin D-dependent intestinal calcium absorption due to impaired renal calcitriol synthesis are largely responsible. Because decreases in serum calcium concentration are a potent and immediate stimulus to PTH secretion and also promote PTH synthesis, correcting this biochemical abnormality during treatment with vitamin D sterols has immediate and beneficial effects to lower plasma PTH levels.^[84] In this context, the classic biologic actions of vitamin D, particularly calcitriol, to enhance intestinal calcium absorption, to raise serum calcium levels, and to correct hypocalcemia represent favorable therapeutic responses, and they are a primary goal of treatment.

Treatment with Daily Oral Doses of Calcitriol or Alfacalcidol

Calcitriol was first introduced for use clinically in the late 1970s, providing a therapeutic intervention un-available previously to offset the crucial defect in renal 1,25-dihydroxyvitamin D production that characterizes patients with CKD. Daily oral doses were used to treat SHPT both in patients with moderate CKD and in those undergoing dialysis regularly. Treatment was begun with small initial doses, typically 0.25 mg/day, and these were adjusted upward periodically either to correct hypocalcemia or to lower plasma PTH levels if serum calcium and phosphorus levels remained within acceptable limits.^[84]

Marked clinical and biochemical improvements were observed during treatment with calcitriol among patients with mild to moderate CKD. Bone pain often diminished, muscle strength improved, and plasma PTH levels decreased.^{[84] [85] [86]} Hypocalcemia, which was common among patients with CKD during an era when calcium-free, phosphate-binding agents such as aluminum hydroxide and aluminum carbonate were used widely, often resolved during treatment.^[85] Histologic features of hyperparathyroidism in bone improved, ^{[87] [88]} and the rate of bone loss from the appendicular skeleton diminished as measured by dual-energy x-ray absorptiometry (DXA).^[88] Indeed, increases in bone mass after oral calcitriol therapy have been reported. ^{[86] [89]} Similar favorable biochemical and histologic responses were reported during treatment with daily oral doses of 1-alpha-hydroxyvitamin D_3, or alfacalcidol, which undergoes 25-hydroxylation in the liver to form calcitriol. ^{[90] [91]}

Several early reports suggested, however, that that the therapeutic use of calcitriol worsened renal function in patients with established CKD. ^{[92] [93]} Most data came from studies that were not controlled adequately, but the potential for adversely affecting renal function during the treatment of SHPT with calcitriol became a widespread concern.^[94] Hypercalcemia during vitamin D therapy can impair renal function by several mechanisms, whereas hypercalciuria increases the risk of nephrolithiasis and nephrocalcinosis. For these reasons, the use of calcitriol either to correct hypocalcemia or to actively treat SHPT among patients with moderate renal failure remained quite limited for many years.

Hypercalcemia and hypercalciuria are uncommon, however, in adults with CKD when the daily dose of calcitriol does not exceed 0.5 mg or when the daily dose of alfacalcidol, or 1-alpha-hydroxyvitamin D₃, does not exceed 0.9 mg.^{[85] [88] [94]} These amounts are often effective in lowering plasma PTH levels, a biochemical response that is due in part to enhanced intestinal calcium absorption and to modest increases in serum calcium concentration. The genomic actions of vitamin D to down-regulate PTH gene transcription and hormone synthesis also contribute. The sustained use of small daily oral doses of calcitriol has been reported to prevent the progressive rise in plasma PTH levels that occurs over time among patients with CKD, stages 3 and 4.^[95] Nevertheless, the therapeutic index for calcitriol in such patients is rather narrow, and serum calcium and phosphorus must be measured regularly to monitor treatment adequately. ^{[84] [96]}

The effectiveness of oral doses of 1-alpha-hydroxyvitamin D_3, or alfacalcidol, for the management of renal bone disease among patients with CKD has been documented quite well. In a large, prospective, randomized clinical trial among patients with creatinine clearances ranging from 15 to 50 ml/min, plasma PTH levels were controlled adequately with daily doses of alfacalcidol ranging from 0.25 mg to 1.0 mg.^[81] In contrast, values increased progressively over 24 months of follow-up among patients given placebo. The histologic features of hyperparathyroidism improved or resolved as assessed by bone biopsy and bone histomorphometry in a substantial proportion of patients treated with alfacalcidol, but they persisted or worsened in those receiving placebo. Interval changes in renal function during 2 years of follow-up did not differ between groups.^[81]

Treatment with Daily Oral Doses of New Vitamin D Sterols

New vitamin D analogs have been introduced as alternatives to calcitriol and alfacalcidol for treating SHPT among patients with CKD who do not require dialysis. ^{[97] [98]} These include doxercalciferol and paricalcitol, which were developed originally for parenteral use in patients undergoing dialysis regularly. Both agents are vitamin D₂ derivatives, and they are available currently as oral preparations in the United States. Results from clinical studies in humans and from work in experimental animal models suggest that these compounds are less potent than calcitriol in promoting intestinal calcium and phosphorus absorption and in raising serum calcium and phosphorus concentrations. ^{[99] [100] [101] [102]} As such, they may have a greater therapeutic index and a more favorable safety profile than calcitriol when used to treat SHPT among patients with mild to moderate CKD, but results from clinical trials that address this issue are quite limited.

Both doxercalciferol and paricalcitol effectively lower plasma PTH levels when used to treat SHPT among patients with CKD, stages 3 and 4 (Figs. 56-6 and 56-7 [6] [7]). ^{[97] [98]} They do so without increasing the serum concentrations of either calcium or phosphorus. In separate placebo-controlled clinical trials, the frequency of episodes of hypercalcemia and/or hyperphosphatemia did not differ between patients treated for 24 weeks with daily oral doses of either doxercalciferol or placebo, or between patients treated for 6 months with daily oral doses of either paricalcitol or placebo. ^{[97] [98]} The biochemical severity of SHPT in the two studies was similar as judged by baseline plasma PTH levels, and pretreatment values for serum calcium and phosphorus concentrations were also quite similar. Calcium excretion in the urine rose modestly during treatment with each compound, but hypercalciuria did not occur with either agent, results due in part to the fact that 24-hour calcium excretion, as expected, was quite low before treatment was begun. Measurements of creatinine clearance also did not change from baseline values during treatment with either doxercalciferol or paricalcitol. ^{[97] [98]}

FIGURE 56-6 The percentage change in plasma parathyroid hormone levels from baseline values during 24 weeks of treatment with either daily oral doses of doxercalciferol or placebo among patients with secondary hyperparathyroidism due to chronic kidney disease, stages 3 or 4. (Reproduced from Coburn JW, Maung HM, Elangovan L, et al: Doxercalciferol safely suppresses PTH levels in patients with secondary hyperparathyroidism associated with chronic kidney disease stages 3 and 4. Am J Kidney Dis 43:877–390, 2004.)

FIGURE 56-7 Plasma parathyroid hormone levels during 24 weeks of treatment with oral doses of paricalcitol or placebo among patients with secondary hyperparathyroidism due to chronic kidney disease, stages 3 or 4. The data represent combined results from three randomized, placebo-controlled clinical trials. Paricalcitol was given orally three times per week in two of the studies, whereas daily oral doses were used in the third. Bars depict the average weekly dose of paricalcitol. (Reproduced from Coyne D, Acharya M, Qiu P, et al: Paricalcitol capsule for the treatment of secondary hyperparathyroidism in stages 3 and 4 CKD. Am J Kidney Dis 47:263–276, 2006.)

Such findings indicate that doxercalciferol and paricalcitol are generally safe and effective for lowering plasma PTH levels and for improving the biochemical control of SHPT among patients with CKD, stages 3 and 4. The impact of treatment with either agent on bone histology has yet to be reported, and the effects of treatment with either doxercalciferol or paricalcitol on bone mass among patients with mild to moderate CKD have not been determined. In contrast, the use of daily oral doses of alfacalcidol as compared with placebo controlled plasma PTH levels better and was associated with greater bone mass, as measured by DXA, after 18 months of follow-up among patients with CKD, stages 3 to 5.^[103] Additional work is needed to characterize adequately the skeletal response to treatment with vitamin D sterols among patients with mild to moderate CKD.

Use of Vitamin D Sterols in Patients with Chronic Kidney Disease Who Require Dialysis

Treatment with Daily Oral Doses of Calcitriol or Alfacalcidol

For many years, oral doses of calcitriol or alfacalcidol represented the only definitive therapeutic intervention for managing SHPT among patients undergoing dialysis regularly. ^{[84] [104]} Daily doses of calcitriol ranging from 0.125 to 0.25 mg, to 0.75 to 1.0 mg were used most often. These doses effectively lowered plasma PTH levels in many patients managed either with hemodialysis or with peritoneal dialysis. ^{[104] [105] [106]} Episodes of hypercalcemia or hyperphosphatemia were common dose-limiting side effects. Although most adult patients tolerated daily oral doses of 0.25 to 0.50 mg of calcitriol without substantial increases in serum calcium concentration, larger amounts frequently raised serum calcium or phosphorus levels. The concurrent use of calcium-containing, phosphate-binding agents and the underlying state of bone remodeling also influenced the risk of developing hypercalcemia during oral calcitriol therapy.

The occurrence of hypercalcemia during oral calcitriol therapy may provide insight into the existing state of skeletal remodeling and the underlying bone pathology. ^{[1] [107]} When hypercalcemia develops after many months of treatment and when previously elevated plasma PTH and alkaline phosphatase levels have decreased and approach normal values, it is likely that the skeletal changes of hyperparathyroidism have resolved substantially or completely. In contrast, episodes of hypercalcemia that occur within the first few weeks of treatment suggest the presence of either low-turnover renal osteodystrophy or severe SHPT.^[1]

During the decade of the 1980s, aluminum-related bone disease most often accounted for low-turnover skeletal lesions, which included both osteomalacia and adynamic renal osteodystrophy.^[1] Measurements of bone aluminum content using either chemical or histochemical methods in bone biopsy specimens were needed to document or to exclude aluminum-related bone disease. For patients with biochemical evidence of severe SHPT, as judged by markedly elevated plasma PTH levels, and for those with histologic evidence of advanced SHPT in bone, parathyroidectomy is required when recurrent episodes of hypercalcemia preclude the safe therapeutic use of oral doses of calcitriol. ^{[1] [108]}

The same factors should be considered when evaluating episodes of hypercalcemia among dialysis patients treated with parenteral doses of vitamin D sterols (vide infra). Hypercalcemia may develop when plasma PTH levels decrease markedly after several months of treatment, a biochemical change that is often associated with substantial reductions in bone remodeling.^[109] Serum calcium concentrations on average are modestly higher in patients with adynamic renal osteodystrophy than in those with other histologic subtypes of renal bone disease due to alterations in the capacity of the skeleton to participate in the physiologic regulation of blood calcium levels.^[110] Bone cell activity is diminished in patients with the adynamic lesion, and episodes of hypercalcemia occur more often in such cases than in patients with SHPT.

Episodes of hypercalcemia during oral calcitriol therapy became more frequent during the decade of the 1980s, when calcium-containing, phosphate-binding compounds replaced aluminum-based compounds as the primary approach to managing hyperphosphatemia among patients undergoing hemodialysis regularly. The effect of calcitriol to enhance intestinal calcium absorption, particularly in persons ingesting large oral doses of calcium, is the most likely explanation for this development. To reduce the risk of hypercalcemia during treatment with vitamin D, the concentration of calcium in dialysate, which before the mid-1980s typically ranged between 3.0 and 3.5 mEq/L, was lowered to 2.5 mEq/L to limit net calcium transfer from dialysate to plasma during each dialysis session. ^{[111] [112]} A dialysate calcium level of 2.5 mEq/L, or 1.25 mmol/L, approximates more closely the normal concentration of ionized calcium in blood in humans.

Treatment with Intermittent Oral Doses of Calcitriol

Twice-weekly or thrice-weekly doses of oral calcitriol have been used to treat SHPT both in patients treated with hemodialysis and in those managed with peritoneal dialysis. ^{[113] [114] [115]} The intermittent administration of calcitriol was thought to lessen the impact of vitamin D therapy on intestinal calcium and phosphorus transport, and to reduce the risk of developing hypercalcemia or hyperphosphatemia. Indeed, somewhat larger cumulative weekly doses of calcitriol can be given using an intermittent as compared with a daily dosing regimen. ^{[116] [117] [118] [119] [120]} Evidence is limited, however, to indicate that twice-weekly or thrice-weekly oral doses of calcitriol are safer or more effective than daily oral doses for managing SHPT among patients receiving peritoneal dialysis.

Treatment with Intermittent Intravenous Doses of Calcitriol

Treatment with intermittent intravenous doses of vitamin D sterols represents the most common approach to managing SHPT among persons treated with hemodialysis in the United States, and oral calcitriol therapy is now used infrequently. By contrast, oral vitamin D therapy continues to be used widely in Europe and elsewhere. Potential advantages of parenteral vitamin D therapy include ensured patient compliance and the ability to deliver larger cumulative weekly doses in an effort to control plasma PTH levels. It has also been suggested that the very high plasma levels that are achieved shortly after bolus intravenous injections of vitamin D sterols enhance their effect to suppress pre-pro-PTH gene transcription and to diminish PTH synthesis in parathyroid tissue.^[121] Evidence to support this contention is quite limited, however, and it remains uncertain whether large intermittent parenteral doses of calcitriol are more effective than daily oral doses for controlling SHPT among patients undergoing hemodialysis.^[122]

Several analogs of vitamin D including calcitriol, paricalcitol, doxercalciferol, and maxacalcitol are available as parenteral preparations that can be given intravenously during each hemodialysis session to treat SHPT. In very short-term studies of adult hemodialysis patients with mild to moderate SHPT, the intravenous administration of calcitriol thrice weekly lowered plasma PTH levels after 2 weeks.^[121] Thrice-weekly doses of calcitriol ranging from 0.5 to 2.25 mg were reported to lower plasma PTH levels by 52% after 12 months and by 71% after 24 months of follow-up in another small study of patients undergoing hemodialysis regularly.^[123] Higher doses can produce greater reductions in plasma PTH levels, but values may fall below the recommended therapeutic target range.^[124] Unfortunately, data about the likelihood of achieving sustained biochemical control of plasma PTH levels after more than 2 years of treatment have not been reported, and the impact of calcitriol therapy on bone mass, on the need for surgical parathyroidectomy, and on skeletal fracture rates is not known.^[125] Patients with marked parathyroid gland enlargement are less likely to respond favorably to treatment with parenteral calcitriol.^[126]

As with oral calcitriol therapy, increases in the serum levels of calcium and phosphorus often limit the doses of parenteral calcitriol that can be given safely to manage SHPT. ^{[121] [123]} These biochemical abnormalities have been associated with adverse clinical outcomes which include morbidity and mortality from cardiovascular causes among patients undergoing dialysis regularly. Recurrent episodes of hypercalcemia are also more likely to occur among patients who use large oral doses of calcium as a phosphate-binding agent. Because of these concerns, parenteral calcitriol therapy has been displaced largely by treatment with new vitamin D compounds such as paricalcitol and doxercalciferol.

Treatment with Intermittent Intravenous Doses of New Vitamin D Sterols

Paricalcitol and doxercalciferol are vitamin D₂ derivatives. Each has been shown to effectively lower plasma PTH levels in short-term studies of patients with biochemical evidence of SHPT. ^{[127] [128] [129]} Serum calcium and phosphorus concentrations increase only modestly during treatment. Paricalcitol and doxercalciferol may thus offer a greater margin of safety for managing SHPT while reducing the risk of potentially serious adverse events such as hypercalcemia and hyperphosphatemia.

Paricalcitol, or 19-nor-1,25-dihydroxyvitamin D₂ is a structurally modified vitamin D₂ analog.^[130] It retains the side-chain that characterizes vitamin D₂ compounds, but it lacks the double bond present normally at the carbon atom located in position 19 of the A ring. When compared with calcitriol, larger doses of paricalcitol are required to raise serum calcium and phosphorus levels in experimental animals with renal failure.^[131] In contrast, equal molar concentrations of paricalcitol and calcitriol have equivalent effects to diminish PTH release from bovine parathyroid cells in tissue culture. ^{[130] [131]} Paricalcitol also appears to be less potent than calcitriol in up-regulating VDR expression in the intestine, a disparity that may account for smaller treatment-related increases in serum calcium concentration in experimental animals given this particular vitamin D sterol.^[100]

Results from one small clinical trial indicate that 12 weeks of treatment with intravenous doses of paricalcitol effectively lowers plasma PTH levels without substantially raising serum calcium or phosphorus concentrations among patients with moderately severe SHPT ( Fig. 56-8 ).^[109] Sustained reductions in plasma PTH levels were reported among patients given paricalcitol for 12 months, although serum calcium and phosphorus levels rose during treatment.^[132] Persistent elevations in serum calcium and phosphorus levels occurred less often among hemodialysis patients treated with paricalcitol than among those given calcitriol in one prospective clinical trial.^[133] Despite these findings, the proportion of patients with SHPT who achieve sustained reductions in plasma PTH levels after treatment with paricalcitol for 2, 3, or 5 years has not been determined. Information about other long-term outcomes, which include skeletal fracture rates and bone mass, is not yet available.

FIGURE 56-8 The percentage reduction in plasma PTH levels from pre treatment values during 12 weeks of treatment with thrice-weekly intravenous doses of paricalcitol among hemodialysis patients with secondary hyperparathyroidism (left panel). Bars indicate the average weekly dose of paricalcitol in micrograpms per kilogram of body weight. Serum calcium and phosphorus concentrations during the study are also shown (right panel). (Reproduced from Martin KJ, Gonzalez EA, Gellens M, et al: 19-Nor-1-a-25-dihydroxyvitamin D2 [paricalcitol] safely and effectively reduces the levels of intact parathyroid hormone in patients on hemodialysis. J Am Soc Nephrol 9:1427–1432, 1998.)

Doxercalciferol, or 1-alpha-hydroxyvitamin D₂, represents the vitamin D₂ equivalent of alfacalcidol, or 1-alpha-hydroxyvitamin D₃. ^{[129] [134]} Doxercalciferol contains the side chain that characterizes vitamin D₂ analogs, but it already bears a hydroxyl group at the carbon atom located at position 1 of the A ring, circumventing the need for 1-alpha-hydroxylation in the kidney. The 25-hydroxylation of doxercalciferol in liver thus produces the biologically more active vitamin D₂ metabolite, 1,25-dihydroxyvitamin D₂. Doxercalciferol is considered to be a prohormone because hepatic metabolism is required to attain full biologic activity.

In rodent assay systems, doxercalciferol is as effective as calcitriol in correcting the skeletal lesions of rickets, in mobilizing calcium from bone, and in enhancing intestinal calcium absorption.^[102] Much higher doses are required, however, to achieve equivalent biologic responses. ^{[135] [136]} In women with osteoporosis, daily oral doses of doxercalciferol exceeding 5 mg/day are required before hypercalciuria develops, whereas increases in calcium excretion in the urine occur typically in such patients with much smaller daily oral doses of calcitriol.^[99] Because doxercalciferol is activated in the liver only after absorption from the gastrointestinal tract, high concentrations of the more potent sterol, 1,25-dihydoxyvitamin D₂, are not present locally within the intestinal lumen. This disparity may account for smaller increases in net intestinal calcium absorption during treatment with oral doses of doxercalciferol as compared with calcitriol.

Treatment with intermittent oral doses of doxercalciferol ranging from 2.5 to 10 mg thrice weekly lowers plasma PTH levels substantially among hemodialysis patients with biochemical evidence of SHPT ( Fig. 56-9 ).^[128] Values decrease by approximately 60% from pretreatment levels after 16 weeks. Serum calcium concentrations rise modestly, and episodes of hypercalcemia and hyperphosphatemia may occur, but these resolve within 3 to 7 days after treatment is withheld temporarily.^[127]

FIGURE 56-9 The percentage change in plasma parathyroid hormone levels from pretreatment values during treatment with thrice-weekly oral doses of doxercalciferol among hemodialysis patients with secondary hyperparathyroidism (left panel). All patients were initially given doxercalciferol for 16 weeks. Patients were then assigned randomly to receive either doxercalciferol or placebo for another 8 weeks. Mean serum calcium and phosphorus concentrations during the study are also shown (right panel). (Reproduced from Frazao JM, Elangovan L, Maung HM, et al: Intermittent doxercalciferol [1a-hydroxyvitamin D2] therapy for secondary hyperparathyroidism. Am J Kidney Dis 36:562–565, 2000.)

The use of intravenous doses of doxercalciferol, ranging from 1 to 4 mg thrice weekly, also effectively lowers plasma PTH levels in hemodialysis patients with overt SHPT ( Fig. 56-10 ).^[127] Treatment with intravenous or oral doses of doxercalciferol is similarly effective for reducing plasma PTH levels, but episodes of hypercalcemia and hyperphosphatemia occur more often with oral therapy.^[129] Accordingly, the intravenous route of drug administration may be preferable for treating SHPT when serum calcium and phosphorus levels are not controlled optimally or when episodes of hypercalcemia or hyperphosphatemia have occurred previously.^[128]

FIGURE 56-10 Plasma parathyroid hormone (PTH) levels (top panel) and the percentage change in plasma PTH (bottom panel) during treatment with thrice-weekly doses of doxercalciferol given orally or intravenously among hemodialysis patients with secondary hyperparathyroidism. Oral doses of doxercalciferol ranged from 2.5 to10.0 mg, whereas intravenous doses ranged from 1.0 to 4.0 mg with each hemodialysis session. (Reproduced from Maung HM, Elangovan L, Frazao JM, et al: Efficacy and side effects of intermittent intravenous and oral doxercalciferol [1-hydroxyvitamin D2] in dialysis patients with secondary hyperparathyroidism: a sequential comparison. Am J Kidney Dis 37:532–543, 2001.)

Additional studies are required to determine whether the frequency of episodes of hypercalcemia and hyperphosphatemia is less during treatment with doxercalciferol than with calcitriol or other vitamin D sterols. The efficacy of doxercalciferol for achieving and for maintaining biochemical control of SHPT among patients treated for many months or several years has not been determined. Similarly, information about the impact of doxercalciferol therapy on bone mass and on skeletal fracture rates among patients undergoing dialysis regularly has yet to be reported.

One of the first vitamin D analogs that was shown to effectively diminish PTH secretion with only limited effects on intestinal calcium transport was 22-oxacalcitriol, or 22-oxa-1,25-dihydroxyvitamin D₃ (OCT).^[137] This structurally modified sterol contains an oxygen atom instead of a carbon atom at position 22 of the side chain of vitamin D₃. In studies of dispersed parathyroid cells in tissue culture, OCT was as effective as calcitriol in decreasing PTH release in vitro.^[138] The administration of single doses of OCT to rats also markedly lowered pre-pro-PTH mRNA expression in parathyroid tissue.^[138]

The affinity of OCT for DBP appears to be less that that of calcitriol.^[139] This difference shortens the half-life of OCT in serum, perhaps reducing its effect to enhance intestinal calcium transport. Tissue-specific differences in the catabolism of OCT by intestinal cells may also affect its biologic actions.^[139] The compound is currently available for use clinically in Japan as maxacalcitol.

Results from several clinical trials using maxacalcitol to treat SHPT among patients undergoing hemodialysis indicate that the drug effectively lowers plasma PTH levels. ^{[140] [141] [142] [143]} The doses used in these studies ranged from 2.5 mg to 20.0 mg intravenously with each thrice-weekly hemodialysis session. Improvements in bone histology have also been reported in small numbers of subjects.^[144] Increases in serum calcium concentrations are not uncommon, however, during treatment with maxacalcitol.^[140] Episodes of hypercalcemia occurred in approximately one third of patients followed for 1 year, but hypercalcemia resolved promptly after doses were reduced or after treatment was withdrawn temporarily.^[140] Clinical trials to assess the frequency of episodes of hypercalcemia or hyperphosphatemia during treatment with maxacalcitol as compared with other vitamin D sterols have not been done.

As discussed previously, vitamin D sterols lower plasma PTH levels among patients with SHPT by inhibiting pre-pro-PTH gene transcription and reducing PTH synthesis in parathyroid tissue. The effect of vitamin D on pre-pro-PTH gene transcription is short-lived, however, and ongoing treatment is required to sustain these responses among patients who respond favorably to vitamin D therapy. Plasma PTH levels often rise substantially after treatment with vitamin D is withdrawn and values return to pre-treatment levels after only a few weeks (see Fig. 56-9 ).^[128] As such, increases in plasma PTH levels are to be expected when vitamin D therapy is withheld temporarily or when doses are reduced among patients with established SHPT. The impact of week-to-week variations in the administered dose of vitamin D must be considered when evaluating plasma PTH levels during the clinical management of SHPT.

Changes in Bone Histology During Treatment with Vitamin D Sterols

Plasma PTH levels, as measured using conventional immunometric assays, provide useful information about the severity of bone disease in untreated patients with SHPT and in those treated with small oral doses of calcitriol. ^{[110] [145] [146]} Marrow fibrosis, increases in the numbers of osteoclasts and other static histologic indices of bone resorption, increases in the number and activity of osteoblasts, and high rates of bone formation are typical when plasma PTH values are elevated substantially. Reductions in plasma PTH levels during treatment with vitamin D sterols are usually accompanied by improvements in these histologic parameters, and values revert toward normal reference values. ^{[147] [148]} Bone formation and turnover may fall substantially, however, during intermittent calcitriol therapy, even when plasma PTH levels remain higher than 300pg/mL, which is the upper limit of the therapeutic target range recommended by the K/DOQI guidelines.^[19] Some patients have bone biopsy evidence of adynamic renal osteodystrophy after treatment with large intermittent doses of calcitriol despite persistently high plasma PTH levels.^[149] Such findings suggest that this therapeutic approach can diminish osteoblastic activity directly and reduce bone formation and bone turnover by PTH-independent mechanisms.

Plasma PTH levels should be monitored regularly during intermittent calcitriol therapy, and the dose of calcitriol should be lowered when serum PTH levels fall to values 4 to 5 times the upper limit of normal to diminish the risk of developing adynamic bone. ^{[106] [149] [150]} Whether other vitamin D analogs such as paricalcitol and doxercalciferol also modify bone formation and turnover in a manner similar to that described during treatment with intermittent doses of calcitriol has is not known. Bone histology data during treatment with these agents have not been reported.

CALCIMIMETIC AGENTS

Calcimimetic agents are small organic molecules that function as allosteric activators of the CaSR, the molecular mechanism that mediates calcium-regulated PTH secretion by parathyroid cells. ^{[151] [152] [153]} One such compound, cinacalcet hydrochloride, is now available for use clinically to treat SHPT among patients undergoing dialysis. Calcimimetic agents bind reversibly to the membrane-spanning portion of the CaSR and lower the threshold for receptor activation by extracellular calcium ions.^[154] In parathyroid tissue, they inhibit PTH secretion directly and lower plasma PTH levels by a mechanism distinct from that of the vitamin D sterols. Calcimimetic compounds thus provide a second, discrete pharmacologic intervention for managing SHPT among persons with CKD. ^{[155] [156]}

Pharmacokinetics and Pharmacodynamics of Cinacalcet

The calcimimetic agent cinacalcet hydrochloride is a hydrophobic compound that is absorbed rapidly from the gastrointestinal tract after oral administration.^[157] Peak plasma levels are attained 60 to 90 minutes after oral doses, and these correspond temporally to the maximum biologic effect, as judged by reductions in plasma PTH levels ( Fig. 56-11 ). ^{[157] [158] [159]} Plasma PTH levels thus fall abruptly after single oral doses of cinacalcet in hemodialysis patients with SHPT, reaching a nadir after 2 to 4 hours. The magnitude of the initial decrease in plasma PTH is largely dose dependent (see Fig. 56-11 ).^[160] Values fall by 60% to 70% from baseline levels after doses of 75 or 100 mg.^[157] Plasma PTH levels rise subsequently, however, toward predose values during the remainder of the day as the concentration of cinacalcet in plasma decreases and as the level of CaSR activation diminishes. ^{[157] [160]}

FIGURE 56-11 The changes in plasma parathyroid levels, expressed as a percentage of predose values, after single oral doses of the calcimimetic agent cinacalcet hydrochloride among hemodialysis patients with secondary hyperparathyroidism. (Reproduced from Goodman WG, Hladik GA, Turner SA, et al: The calcimimetic agent AMG 073 lowers plasma parathyroid hormone levels in hemodialysis patients with secondary hyperparathyroidism. J Am Soc Nephrol 13:1017–1024, 2002.)

Plasma PTH levels decrease invariably following the administration of calcimimetic agents.^[161] Persons who fail to respond in this matter have yet to be identified even among patients with clinical disorders where the level of expression of the CaSR in parathyroid tissue is known to be reduced. These persons include patients with SHPT due to parathyroid gland hyperplasia and those with primary hyperparathyroidism due to parathyroid adenoma. ^{[158] [159] [160] [162] [163]}

Treatment with daily doses of cinacalcet thus produces an oscillating hormone concentration profile during the day.^[161] This pattern differs strikingly from the relatively constant levels of PTH in plasma throughout the day, which includes changes due to pulsatile hormone secretion, that characterize persons with normal renal and parathyroid gland function, untreated patients with SHPT due to CKD, and those receiving stable doses of vitamin D sterols to manage SHPT.^[164] It is important to recognize these short-term variations in plasma PTH levels among cinacalcet-treated patients when monitoring the biochemical response to therapy.^[155]

Because plasma PTH levels decrease substantially but rise subsequently after oral doses of cinacalcet, variations in the interval between drug administration and the collection of blood samples for measurements of plasma PTH levels will affect the values obtained.^[155] Measurements determined in samples collected shortly after daily oral doses will reflect nearly maximum pharmacologic effects of the drug on CaSR activation, and plasma PTH levels will be reduced substantially.^[163] In contrast, measurements obtained in blood samples collected 12 to 24 hours later will show smaller decreases from predose values. In this regard, all clinical trials reported thus far among patients with CKD have used plasma PTH levels obtained 24 hours after the preceding dose of cinacalcet to assess the biochemical efficacy of treatment and to guide decisions about dosage adjustments. ^{[155] [161] [165] [166]}

When using cinacalcet for the clinical management of patients with SHPT, it is generally recommended that plasma PTH levels be measured at least 12 hours after the preceding dose. Such an approach thus provides biochemical information similar to that used in published clinical trials to guide decisions about dosage adjustments and to judge therapeutic efficacy. ^{[155] [165]}

Apart from reducing plasma PTH levels, treatment with calcimimetic agents lowers serum calcium concentrations modestly.^[163] Serum total and blood ionized calcium levels decrease during the first 12 to 24 hours after treatment is begun, changes that temporally follow an abrupt initial decline in plasma PTH as described previously.^[163] Values stabilize within 24 to 48 hours, however, and serum calcium concentrations do not fall progressively if the dose remains unchanged. ^{[160] [163]} Such findings thus underscore the crucial role of short-term variations in PTH secretion by the parathyroid glands in maintaining the level of ionized calcium in blood. Reductions in serum calcium concentration are thus a predictable, physiologic response to treatment with calcimimetic agents.

Nevertheless, the use of large initial doses of cinacalcet or the continued administration of cinacalcet without periodic dosage adjustments based upon repeated measurements of serum calcium concentrations can result in symptomatic hypocalcemia or overt tetany.^[155] For these reasons, a dose titration scheme is used when treatment is begun.^[165] Daily doses of 30 mg of cinacalcet are used initially, and these doses are increased subsequently in increments of 30 mg at 2- or 3-week intervals to a maximum daily dose of 180 mg if serum calcium concentrations remain within acceptable limits and when substantial reductions in serum calcium concentration have been excluded by periodic measurements. The safety of this approach has been documented in large clinical trials in which symptomatic hypocalcemia did not occur.^[165]

The pharmacokinetic profile of cinacalcet changes in a linear fashion with doses up to 200 mg. Larger daily doses do not increase drug exposure further.^[157] Neither the pharmacokinetics nor pharmacodynamics of cinacalcet is affected by hemodialysis procedures.^[167] The half-life of cinacalcet in plasma is approximately 30 hours, both in patients with CKD and in those with normal renal function. Based upon these considerations, all published clinical trials have used single daily oral doses of cinacalcet to treat SHPT among patients undergoing dialysis. The impact of more frequent dosing regimens on plasma PTH levels and on serum calcium and phosphorus concentrations has yet to be reported among patients with SHPT.

Use of Cinacalcet in Patients Undergoing Dialysis

Clinical Efficacy

The efficacy of cinacalcet for treating SHPT among patients undergoing hemodialysis has been documented adequately.^[165] As noted previously, plasma PTH levels fall invariably within a few hours after the administration of cinacalcet, and sustained reductions in plasma PTH are achieved during treatment with daily oral doses for 12 to 18 weeks. ^{[168] [169]} Plasma PTH levels declined by an average of 25% to 40% from baseline, or pretreatment, values in studies that used maximum daily doses of 100 to 120 mg, whereas larger percentage reductions were achieved using daily doses as high as 180 mg.^[157] Serum calcium and phosphorus levels also decreased modestly during treatment.

In one large clinical trial, treatment with cinacalcet was begun in patients with inadequately controlled SHPT despite previous management with vitamin D sterols and phosphate-binding agents.^[165] Approximately two thirds of patients continued to receive constant doses of vitamin D sterols during the trial, and the dose of cinacalcet was titrated upward to lower plasma PTH levels. The remaining one third of patients did not receive concurrent vitamin D therapy, often because the serum levels of calcium or phosphorus were not controlled adequately, thus precluding the safe therapeutic use of vitamin D. Daily doses of cinacalcet were again raised incrementally to lower plasma PTH levels.^[165]

Plasma PTH levels declined substantially during 26 weeks of treatment ( Fig. 56-12 ). Overall, the proportion of patients who achieved biochemical control of SHPT, as judged by PTH levels equal to or less than 250pg/mL, increased progressively during 26-weeks of follow-up ( Fig. 56-13 ).^[165] Forty-one percent of patients reached this therapeutic end-point, whereas plasma PTH levels decreased by 30% or more in more than 70% of study participants.

FIGURE 56-12 Mean plasma parathyroid hormone (PTH) levels during 26 weeks of treatment with cinacalcet or placebo among hemodialysis patients with secondary hyperparathyroidism (A). The percentage change in plasma PTH values as determined using a first-generation immunometric PTH assay (IMA) that detects both PTH(1-84) and other amino terminally truncated fragments of PTH(1-84) is depicted (B), together with results obtained using a second-generation IMA assay that detects PTH(1-84) exclusively in a subset of patients (C). (Reproduced from Block GA, Martin KJ, De Francisco ALM, et al: The calcimimetic cinacalcet hydrochloride for the treatment of secondary hyperparathyroidism in patients receiving hemodialysis. N Engl J Med 350:1516–1525, 2004.)

FIGURE 56-13 The percentage of patients treated for 26 weeks with cinacalcet or placebo who achieved a mean plasma parathyroid hormone (PTH) level less than 250pg/mL or a decrease in plasma PTH equal to or greater than 30% (A). The proportion who achieved a plasma PTH level less than 250pg/mL increased progressively during the study (B), and the fraction of cinacalcet-treated patients that experienced a 30% or greater decrease in plasma PTH levels from pretreatment values did not differ according to disease severity as judged by baseline, or pre-treatment, plasma PTH determination (C). (Reproduced from Block GA, Martin KJ, De Francisco ALM, et al: Cinacalcet for secondary hyperparathyroidism in patients receiving dialysis. N Engl J Med 350:1516–1525, 2004.)

The efficacy of cinacalcet for lowering plasma PTH levels does not differ according to disease severity as judged by baseline PTH values (see Fig. 56-13 ). ^{[165] [170]} Cinacalcet thus appears to be equally effective among patients with mild, moderate, or advanced SHPT. Although CaSR expression is diminished in hyperplastic parathyroid tissue from patients with overt SHPT, such changes do not modify the ability of cinacalcet to produce sustained reductions in plasma PTH levels that are meaningful clinically.^[171]

Available data indicate that cinacalcet can be used either alone as a primary intervention or together with vitamin D sterols to control plasma PTH levels among patients with SHPT.^[165] Its effectiveness in lowering plasma PTH levels is not affected substantially by the concurrent use of constant doses of vitamin D sterols.^[165] The changes in serum calcium and phosphorus levels during treatment with cinacalcet are also largely unaffected by the concurrent use of stable doses of vitamin D or by the concurrent administration of either calcium-containing or calcium-free phosphate-binding agents. Substantive adjustments to the doses of vitamin D sterols were precluded, however, by the treatment protocols used in most published clinical trials.^[155] Such findings thus do not describe fully the potential impact of frequent adjustments to the doses of vitamin D, as occurs commonly in clinical practice, on the biochemical responses to treatment with cinacalcet. Additional work is needed to clarify this issue.

Biochemical Outcomes

Controlling serum phosphorus levels adequately is difficult in patients with CKD, stage 5, who require treatment with hemodialysis or peritoneal dialysis.^[172] To a considerable extent, the problem is attributable to the limited amounts of phosphorus that can be removed by thrice-weekly hemodialysis or by peritoneal dialysis. As a result, intestinal phosphorus absorption from dietary sources usually exceeds the amount that can be removed weekly from plasma by dialysis, and total body phosphorus balance remains positive even among patients who ingest phosphate-binding agents regularly. These shortcomings lead ultimately to phosphorus retention and to hyperphosphatemia, which can aggravate SHPT. Persistent hyperphosphatemia often precludes the regular use of vitamin D sterols to control plasma PTH levels among patients with SHPT because of concerns about the potential for vitamin D therapy to worsen soft tissue and vascular calcification.

In addition, SHPT can aggravate hyperphosphatemia by promoting phosphorus mobilization from bone in persons with little or no residual renal function.^[173] Inadequate control of SHPT is thus another factor that can undermine efforts to manage hyperphosphatemia among patients undergoing dialysis regularly.^[174] The use of large oral doses of calcium to control serum phosphorus levels may also lead to episodes of hypercalcemia, further complicating clinical management and precluding the consistent therapeutic use of vitamin D sterols to control plasma PTH levels. For these reasons, it is difficult to maintain serum calcium and phosphorus levels within the stringent limits advocated by the K/DOQI guidelines while treating SHPT using conventional therapeutic approaches even among patients with mild to moderate SHPT. ^{[12] [18]}

In this context, the ability of cinacalcet to lower plasma PTH levels without aggravating phosphorus retention or raising serum calcium concentrations is of considerable interest. Because cinacalcet does not raise serum calcium or phosphorus levels and indeed often lowers the level of these two biochemical parameters, it can be given therapeutically to reduce plasma PTH levels even when serum calcium and phosphorus levels are elevated, disturbances that preclude the safe use of vitamin D sterols. Cinacalcet therapy has been reported to increase the fraction of patients with SHPT, predominantly those managed by hemodialysis, whose plasma PTH levels are controlled adequately while maintaining serum calcium and phosphorus levels within the ranges recommended by the K/DOQI guidelines.^[175] It remains to be determined, however, whether these favorable biochemical responses are associated with better clinical outcomes, particularly as regards vascular and soft tissue calcification among patients undergoing dialysis regularly.

Sustained reductions in plasma PTH levels have been reported in patients treated with cinacalcet for as long as 3 years. ^{[166] [176]} Long-term treatment thus does not appear to modify signal transduction through the CaSR or attenuate the effect of daily doses of cinacalcet to lower plasma PTH levels in patients with SHPT.^[171]

Clinical Outcomes

Preliminary information suggests that cinacalcet therapy reduces the need for surgical intervention with parathyroidectomy to definitively control SHPT among patients undergoing dialysis.^[177] Such findings are consistent with results obtained in several animal models indicating that the administration of calcimimetic agents diminishes cell proliferation in parathyroid tissue and retards parathyroid gland enlargement. ^{[178] [179]} Treatment with cinacalcet may also diminish the risk of skeletal fracture among patients with SHPT who require dialysis regularly.^[177] Prospective clinical trials are needed to confirm these findings. The impact of calcimimetic therapy on the development and progression of vascular calcification among patients with CKD has not been examined.

Reductions in bone mass, particularly in cortical bone, are common both in patients with primary hyperparathyroidism and in those with SHPT due to CKD. Bone mass is often reduced substantially in patients with CKD when renal replacement therapy is initiated. ^{[180] [181]} Persistently elevated plasma PTH levels are thought to be largely responsible. Cyclic variations in plasma PTH levels during the day as occur during treatment with daily oral doses of cinacalcet may, however, have anabolic, or trophic, effects on bone metabolism and favorable effects on skeletal mass. ^{[135] [182] [183]} Preliminary data in a small number of dialysis patients with SHPT suggest that bone mass increases as measured by DXA after 12 months of treatment.^[184] Additional studies are needed to validate these findings.

Clinical Management

Serum calcium levels decline modestly and consistently during treatment with cinacalcet, but marked decreases are infrequent. ^{[160] [165] [168] [169]} Symptomatic hypocalcemia does not occur when patients are managed using the dose-titration scheme described previously and employed consistently in published clinical trials.^[165] Nevertheless, serum calcium concentrations less than 7.5 to 8.0 mg/dL are not uncommon during treatment with cinacalcet, and measures to correct this biochemical change are often undertaken. These include treatment with vitamin D sterols, increases in dose of vitamin D for patients already receiving these compounds, increases in the concentration of calcium in dialysate, and increases in oral calcium intake, either as calcium supplements or as calcium-containing, phosphate-binding compounds. Each of these interventions must be undertaken with caution, however, and they may be unsuitable or inappropriate.

Treatment with cinacalcet in patients with SHPT due to CKD, stage 5, produces a physiologic state in parathyroid tissue similar to that of patients with activating mutations of the CaSR.^[185] Persons with the syndrome of familial hypocalcemia are generally asymptomatic, but basal serum calcium concentrations are lower than normal due to activating mutations of the CaSR.^[185] Such individuals thus modulate PTH secretion in a physiologic manner around a relatively low blood ionized calcium concentration as compared with subjects with normal parathyroid gland function. Plasma PTH levels become suppressed markedly, however, when treatment with oral calcium supplements or vitamin D sterols is undertaken to raise serum calcium concentrations toward normal. As a result, calcium excretion in the urine increases substantially, and hypercalciuria develops. Such changes can lead to nephrolithiasis or nephrocalcinosis, or both, with adverse effects on renal function.^[185]

Calcium excretion in the urine increases as serum calcium concentrations rise among patients with familial hypocalcemia, in part, because the mutant activated CaSR in the thick ascending limb of the loop of Henle diminishes calcium reabsorption within this nephron segment. However, calcium-mediated reductions in plasma PTH levels during treatment with calcium or vitamin D further increase renal calcium excretion in such patients.^[185]

Among patients with SHPT due to CKD who have little or no residual renal function, the effect of calcimimetic agents on renal tubular calcium transport has little functional importance. Nevertheless, raising serum calcium concentrations produces sustained reductions in plasma PTH levels among dialysis patients who are already receiving cinacalcet for the treatment of SHPT because parathyroid tissue has been rendered more sensitive to the inhibitory effect of calcium on PTH secretion. In the absence of renal mechanisms for increasing calcium excretion, inadvertent calcium loading will occur. This may lead to calcium retention with the attendant risks of soft-tissue and vascular calcification.

In the absence of kidney function, minute-to-minute variations in PTH secretion regulate blood ionized calcium levels by modulating the exchange of calcium between bone and plasma, whereas persistent reductions in PTH secretion diminish the capacity of the skeleton to accommodate additional amounts of calcium that enter the extracellular fluid by reducing calcium uptake into bone.^[186] Such changes may increase the likelihood of extraosseous calcification in persons with advanced CKD.^[187]

Additional work is needed to assess the long-term consequences, if any, that arise from the modest reductions in serum calcium levels that occur during cinacalcet therapy, particularly as regard bone metabolism. Preliminary results suggest that 12 months of treatment with cinacalcet does not adversely affect skeletal mineralization as judged by quantitative bone histology in patients undergoing dialysis regularly. Further work is needed, however, to characterize adequately the impact of treatment with cinacalcet on bone histology among patients with SHPT.

Use of Cinacalcet in Patients with Chronic Kidney Disease Who Do Not Require Dialysis

The efficacy of cinacalcet for treating SHPT has been evaluated in fewer patients with CKD, stages 3 and 4, and the drug is not currently approved for use clinically in persons with mild to moderate renal insufficiency. Treatment with daily oral doses of cinacalcet does, however, lower plasma PTH levels among patients with CKD, stages 3 and 4 ( Fig. 56-14 ). In contrast to patients with CKD, stage 5, serum phosphorus levels increase modestly, although values generally remain within the normal range (see Fig. 56-14 ).^[188] A decrease in the fractional excretion of filtered phosphorus due to cinacalcet-mediated reductions in plasma PTH levels most likely accounts for this biochemical finding.

FIGURE 56-14 The percentage change in plasma PTH levels from pretreatment values during 18 weeks of treatment with cinacalcet or placebo among patients with secondary hyperparathyroidism due to CKD, stages 3 or 4 (top panel). Corresponding changes in serum phosphorus concentrations during the study are also shown (bottom panel). (Reproduced from Charytan C, Coburn JW, Chonchol M, et al: Cinacalcet hydrochloride is an effective treatment for secondary hyperparathyroidism in patients with CKD not receiving dialysis. Am J Kidney Dis 46:58–67, 2005.)

SHPT is common among patients with mild to moderate CKD, and plasma PTH levels increase progressively as renal function declines.^[6] Values are elevated substantially in many patients when treatment with regular dialysis is begun.^[180] In this regard, therapeutic interventions that are undertaken at earlier stages of CKD may be important for retarding disease progression. The effect of cinacalcet to diminish parathyroid gland hyperplasia in experimental animal models of SHPT suggests that calcimimetic agents may be useful for this purpose. ^{[178] [179] [189] [190]} Nevertheless, the impact of treatment with cinacalcet on parathyroid gland hyperplasia and on disease progression has not been examined in clinical studies of patients with mild to moderate CKD due largely to technical difficulties in obtaining reliable measurements of parathyroid gland size.

PHOSPHATE-BINDING AGENTS

Phosphorus Metabolism in Chronic Kidney Disease

Phosphorus retention and hyperphosphatemia develop in virtually all patients with advanced CKD because phosphorus excretion in the urine is insufficient to offset the amounts absorbed daily from dietary sources. Recurrent episodes of hyperphosphatemia or persistent elevations in serum phosphorus levels are common among patients undergoing dialysis regularly, and values exceeding 6 to 7 mg/dL are not unusual. ^{[11] [191]} As noted previously, only limited amounts of phosphorus can be removed using traditional dialysis strategies, resulting in net cumulative weekly phosphorus retention among patients managed with either peritoneal dialysis or conventional thrice-weekly hemodialysis. The importance of these technical constraints is underscored by the findings that hyperphosphatemia often resolves and that dietary phosphorus supplements may be required to correct hypophosphatemia among patients treated with alternative dialysis strategies such as daily, nocturnal hemodialysis, which markedly increases cumulative weekly phosphorus removal.^[192]

In contrast to those with CKD, stage 5, serum phosphorus levels are within the normal range in most patients with less advanced renal failure.^[16] Values exceed the upper limit of normal in only a small minority of patients with CKD, stages 3 or 4. Several factors account for these findings. These factors include the large amounts of phosphorus filtered continuously at the glomerulus and the considerable capacity of cells of the proximal nephron to modify fractional phosphorus reabsorption and to modulate phosphorus excretion in the urine.^[193] Some of the changes in phosphorus transport in the proximal tubule occur quite rapidly following changes in dietary phosphorus intake, and they are due to alterations in the localized expression of sodium-phosphate co-transport proteins within the apical membrane of proximal tubular cells. Hormonal factors such as PTH and FGF-23 also exert striking effects on proximal tubular phosphorus transport, again by modulating sodium-phosphate co-transporter expression and activity. ^{[194] [195] [196]}

The peptide hormone FGF-23 has been recognized increasingly as an important regulator of systemic phosphorus homeostasis.^[194] Serum FGF-23 levels rise progressively as renal function declines, and this change may contribute substantially to decreases in fractional phosphorus reabsorption in the proximal nephron and to increases in the fractional excretion of filtered phosphorus in patients with CKD. ^{[2] [197]} In addition, FGF-23 diminishes renal calcitriol synthesis and may contribute further to the low serum levels of calcitriol that characterize patients with progressive CKD. ^{[198] [199]}

In patients with little or no residual renal function and particularly those who require treatment with dialysis, serum phosphorus levels are usually elevated, but values vary substantially from day to day due to short-term changes in dietary phosphorus intake.^[200] As a result, phosphorus-restricted diets and phosphate-binding medications are used regularly. Reducing the dietary phosphorus content leaves less available for absorption by the small intestine, whereas phosphate-binding agents form insoluble complexes with phosphorus within the lumen of the gastrointestinal tract and diminish net phosphorus absorption.

Therapeutic Objectives

The primary goals of treatment are to control serum phosphorus levels adequately, to reduce the frequency and severity of episodes of hyperphosphatemia, and to limit the risk of soft tissue calcification, particularly vascular calcification.^[201] Hyperphosphatemia can also aggravate SHPT and contribute to disease progression.^[202] Elevated serum phosphorus levels have been identified in observational studies as a risk factor for cardiovascular disease and for mortality among patients undergoing hemodialysis regularly. ^{[12] [18] [202]} Adequate control of this biochemical parameter is thus recognized increasingly as an essential component of the clinical management of patients with CKD.

The range of values for serum phosphorus concentrations that are considered to be acceptable are now lower than those used previously. ^{[19] [191]} Current recommendations, as set forth in the K/DOQI guidelines, are to maintain serum phosphorus levels within the normal reference range among patients with CKD, stages 3 and 4. For patients with CKD, stage 5, including those treated with dialysis, values between 3.5 and 5.5 mg/dL are considered acceptable.^[19]

Phosphate-binding agents diminish intestinal phosphate absorption by forming poorly soluble complexes with phosphorus in the intestinal lumen ( Fig. 56-15 ). They are most effective when ingested with meals to permit admixture with foods and to optimize phosphorus binding. In the past, aluminum-containing medications such as aluminum hydroxide and aluminum carbonate were employed widely. Both were potent phosphate-binding compounds, but their long-term use led to aluminum retention and aluminum toxicity due to ongoing intestinal aluminum absorption.^[203] As such, these agents should be used sparingly, if at all, to manage phosphorus retention in patients with CKD. If they are used, the duration of treatment should be limited to periods of 2 to 3 months, and doses should be kept as low as possible. The concurrent administration of citrate-containing compounds must be avoided because citrate markedly enhances intestinal aluminum absorption. ^{[204] [205]} Plasma aluminum levels should be monitored regularly in patients who are given aluminum-containing medications.

FIGURE 56-15 A schematic diagram illustrating the mechanism by which phosphate-binding agents diminish intestinal phosphorus absorption. Cations such as calcium, lanthanum, and aluminum form insoluble salts with phosphate ions within the lumen of the small intestine, thus leaving lesser amounts of unbound phosphorus available for absorption. Sevelamer is an nonabsorbable synthetic polymer that acts as an ion exchange resin to sequester phosphate ions.

Calcium-Binding Compounds

Calcium carbonate and calcium acetate are both used widely as phosphate-binding agents. The clinical efficacy of the two compounds is similar. Calcium citrate has also been used as a phosphate-binding agent, but citrate can enhance intestinal aluminum absorption in patients who are also receiving aluminum-containing compounds. ^{[205] [206]} It is used infrequently.

Calcium-containing salts are effective in lowering serum phosphorus levels among patients with advanced CKD, but very large doses are required.^[13] The total amount of elemental calcium ingested daily in patients who use calcium-containing compounds exclusively often exceeds 1200 mg, the amount recommended generally for persons in the general population. It may be as much as 4 to 6 g of elemental calcium per day or more.

Although active, vitamin D-dependent intestinal calcium transport is diminished among patients with CKD due largely to impaired renal calcitriol synthesis as discussed previously, the absorption of calcium by passive mechanisms is unregulated and increases as a function of the amount of ingested. ^{[13] [207]} Episodes of hypercalcemia are quite common among dialysis patients who use either calcium carbonate or calcium acetate exclusively as a phosphate-binding agent because the capacity to excrete calcium in the urine is reduced markedly or absent completely.^[173] The concurrent administration of vitamin D sterols further increases this risk.^[173]

The use of very large oral doses of calcium as a phosphate-binding agent has been associated with evidence of soft tissue and vascular calcification among patients undergoing long-term dialysis. ^{[208] [209] [210]} It may also be a risk factor for the syndrome of calciphylaxis and for progressive vascular calcification among patients receiving dialysis regularly. ^{[210] [211] [212]} Treatment with calcium-containing compounds is also more frequent among patients with adynamic renal osteodystrophy than in those with other histologic subtypes of renal bone disease.^[213] Such findings suggest that the continuous administration of large amounts of calcium to patients with CKD, stage 5, can lower plasma PTH levels and diminish bone remodeling.

Based upon these observations, alternative phosphate-binding strategies that limit total calcium intake to 1500 to 2000 mg/day from both dietary and medicinal sources have been developed.^[191] The K/DOQI guidelines for managing bone disease and mineral metabolism among patients with CKD recommend that the total daily intake of calcium not exceed 2000 mg for patients undergoing dialysis regularly.^[19] Unfortunately, this often precludes the use of calcium-containing compounds at doses sufficient to control serum phosphorus concentrations adequately in patients who require renal replacement therapy. Phosphate-binding agents that do not contain calcium are thus required to achieve this therapeutic objective. Apart from compounds that contain aluminum, sevelamer hydrochloride and lanthanum carbonate are the only calcium-free phosphate-binding agents approved currently for use clinically to manage hyperphosphatemia among patients with CKD, stage 5.

Calcium-Free Compounds

Sevelamer, or hydrogel of cross-linked poly-allylamine hydrochloride, is a synthetic polymer that binds phosphorus within the lumen of the gastrointestinal tract and reduces its absorption. ^{[214] [215] [216] [217]} It does not contain either calcium or aluminum. In short-term clinical trials, sevelamer has been shown to be as effective as calcium acetate for controlling serum phosphorus levels with substantially fewer episodes of hypercalcemia.^[218] In longer term studies, total daily doses averaging 5 to 6 g were sufficient to maintain serum phosphorus levels at approximately 5.8 to 6.0 mg/dL, or 1.8 to 2.0 μM, among patients undergoing hemodialysis regularly.^[219] Larger doses may be required to achieve the more stringent therapeutic targets for serum phosphorus levels outlined in the K/DOQI guidelines.

Interestingly, the serum levels of total cholesterol and low-density lipoprotein decrease by 20% to 30% during treatment with sevelamer, whereas high-density lipopoprotein levels rise. ^{[214] [219] [220]} These biochemical changes represent potentially favorable side effects of therapy among patients who have a risk profile for cardiovascular disease that is extremely high. Among patients with CKD who do not require dialysis, serum carbon dioxide levels decrease modestly during treatment, a biochemical change that is probably due to the release of protons from the resin during phosphate binding.^[221]

In one prospective clinical trial, patients undergoing hemodialysis who were managed with calcium-containing, phosphate-binding agents had evidence of progressive vascular calcification as measured by electron beam computed tomography after 12 months of follow-up.^[222] In contrast, coronary artery and aortic calcification scores did not change among patients given sevelamer. The factors that account for these differences remain uncertain. Although serum phosphorus levels during study did not differ between groups, serum calcium levels were higher and plasma PTH levels were lower among patients receiving calcium.^[222] Such findings suggest that the continuous use of large oral doses of calcium can affect calcium metabolism systemically among patients undergoing dialysis, most probably by increasing net intestinal calcium absorption through passive mechanisms.

Lanthanum carbonate is a potent phosphate-binding agent that is now available for use clinically among patients undergoing dialysis.^[223] The capacity of this compound to bind phosphorus in vitro is similar to that of aluminum hydroxide, and it is greater than that of calcium acetate, calcium carbonate, and sevelamer.^[224] Clinical trials with lanthanum carbonate using doses as high as 3000 mg per day document its efficacy in lowering serum phosphorus levels among patients undergoing dialysis. ^{[225] [226] [227] [228]}

A very small fraction of ingested lanthanum is absorbed from the gastrointestinal tract, and trace amounts are detectable in various tissues, including liver and bone. Histologic studies of bone in biopsies obtained after 1 year of treatment with lanthanum carbonate show no adverse effects on skeletal mineralization or on bone remodeling among patients managed with hemodialysis.^[229] Safety and efficacy have been documented among patients treated for as long as 3 years.^[228] Additional work is needed, however, to determine whether there is ongoing lanthanum accumulation in bone or other tissues with long-term treatment.^[229]

Calcium supplements

If calcium-free, phosphate-binding agents are used exclusively to manage hyperphosphatemia among patients with CKD, the diet becomes the sole source of calcium to satisfy nutritional requirements, except for amounts that may be transferred from dialysate to plasma during either hemodialysis or peritoneal dialysis procedures. Because phosphorus-restricted diets contain only limited amounts of calcium, oral calcium supplementation may be necessary to achieve a daily intake of 1000 to 1200 mg. Unfortunately, few studies have addressed issues of calcium nutrition among patients with CKD, and there is only limited information to define the proper level of dietary calcium intake either for patients with mild to moderate CKD or for those with CKD, stage 5, who are treated with dialysis.

Oral calcium supplementation is used in some patients with mild to moderate CKD to maintain adequate calcium nutrition. Such an approach, either alone or together with small oral doses of vitamin D sterols, is often effective in raising serum calcium concentrations and in correcting hypocalcemia among patients with CKD, stages 3 and 4, whose serum calcitriol levels are often reduced. Large doses of calcium should be avoided, however, and calcium excretion in the urine should be monitored to avoid hypercalciuria.

The use of oral calcium supplements among patients with mild to moderate CKD differs fundamentally from the administration of very large doses of calcium-containing, phosphate-binding agents among patients with CKD, stage 5. Much smaller doses are given, and the presence of residual renal function allows excess amounts of calcium that may be absorbed to be excreted. ^{[13] [208]}

Management of bone disease, mineral metabolism, and parathyroid gland function

The clinical management of SHPT, renal bone disease, and the disturbances in calcium and phosphorus metabolism associated with CKD is challenging. Ongoing efforts are required to control a number of biochemical abnormalities, some of which are associated with adverse clinical outcomes. The benefits and risks associated with each therapeutic intervention should be considered carefully.

Certain interventions such as the use of large intravenous doses of vitamin D sterols to control plasma PTH levels, inappropriate treatment with vitamin D among patients who do not have SHPT, and the use of large oral doses of calcium as a phosphate-binding agent can raise serum calcium levels, leading to episodes of hypercalcemia. Serum phosphorus levels may rise during treatment with vitamin D sterols, resulting in episodes of hyperphosphatemia. These biochemical abnormalities can aggravate soft tissue and vascular calcification. The availability of calcium-free, phosphate-binding agents circumvents the need to use supraphysiologic doses of calcium to manage phosphorus retention among patients with CKD, but additional measures may then be required to ensure adequate calcium nutrition. The historic experience with aluminum-containing and calcium-containing, phosphate-binding compounds mandates ongoing vigilance to identify adverse outcomes when using large amounts of any therapeutic agent for extended periods among patients with little or no residual renal function.

Treatment with calcimimetic compounds specifically targets the molecular mechanism that regulates PTH secretion, and the use of this new class of therapeutic agents effectively reduces plasma PTH levels and often lowers serum calcium and phosphorus levels among patients with SHPT. The impact of these biochemical changes on bone histology, bone cell activity, and bone mass among patients with renal osteodystrophy has yet to be defined fully. Vitamin D sterols effectively diminish PTH synthesis and lower plasma PTH levels, but their efficacy for achieving sustained biochemical control of SHPT and in favorably modifying outcomes with regard to bone mass, skeletal fracture rates, and the need for surgical parathyroidectomy has not been established.^[125] More fundamental matters with respect to vitamin D nutrition and its importance, both among patients with mild to moderate CKD and among those with CKD, stage 5, who are treated with dialysis, remain largely unresolved.^[230]

To maximize benefit and to limit risks, the management of various disturbances in bone and mineral metabolism, including SHPT, requires interventions that are directed at specific therapeutic targets to achieve clinical and biochemical outcomes that have been defined clearly. These include optimizing calcium and phosphorus metabolism, controlling parathyroid gland function, and maintaining skeletal health. Treatment relies predominantly upon the judicious use of four pharmacologic agents, namely calcium-containing, phosphate-binding compounds, calcium-free phosphate-binding, agents, vitamin D sterols and calcimimetic agents. No single therapeutic intervention should be expected to be sufficient alone for clinical management, and several are usually required. The use of any one of them should be based upon a fundamental understanding of the underlying pathophysiology and the suitability and appropriateness of the intervention proposed to correct it.

Specific therapeutic considerations

Chronic Kidney Disease, Stages 2, 3, and 4

Phosphate-Binding Agents and Calcium Metabolism

Phosphorus-restricted diets mandate that the intake of dairy products be limited substantially. The calcium content of such diets is often in the range of 500 to 600 mg. Modest dietary calcium supplementation is thus required in many patients with CKD to achieve a total daily calcium intake of 1000 to 1200 mg as recommended by the World Health Organization. Other medicinal sources of calcium should be considered, however, when evaluating the nutritional needs for calcium among patients with CKD. The amounts of calcium ingested as calcium-containing, phosphate-binding compounds must be recognized as an additional source of dietary calcium.

Calcium excretion in the urine is reduced in most patients with CKD stages, 3 or 4, a finding that reflects an overall decrease in the efficiency of intestinal calcium absorption. ^{[97] [98]} The judicious use of modest oral doses of calcium in such patients may thus serve to maintain serum calcium concentrations, correct overt hypocalcemia, and avert compensatory secretory responses by the parathyroid glands to maintain calcium homeostasis as renal function declines. Adequate calcium-dependent signaling through the CaSR may be particularly important in preventing the development of SHPT and in retarding the progression of parathyroid gland hyperplasia. ^{[178] [179] [189]} The efficacy of such an approach has not been examined critically, however, in prospective clinical trials among patients with mild to moderate CKD. Calcium excretion in the urine should be measured periodically among patients treated with oral calcium supplements, and doses should be adjusted to avoid hypercalciuria.

If serum phosphorus levels are elevated, treatment with calcium carbonate or calcium acetate to control serum phosphorus levels provides additional calcium to supplement that available from dietary sources. Calcium that does not form insoluble complexes with phosphorus within the lumen of the intestine remains available for absorption. The use of modest doses of calcium-containing, phosphate-binding compounds thus addresses concurrently the need to optimize calcium nutrition and to control serum phosphorus levels among patients with CKD stages, 3 or 4.

Although hyperphosphatemia is uncommon among patients with mild to moderate CKD, plasma PTH are often elevated. ^{[6] [16]} Dietary phosphorus restriction and the use of phosphate-binding agents are the first therapeutic interventions recommended by the K/DOQI guidelines for achieving reductions in plasma PTH levels among patients with CKD, stages 2 through 4, even when serum phosphorus concentrations remain within the normal range.^[19]The PTH-lowering effect of calcium-containing compounds in this clinical context is due, in part, to increases in intestinal calcium absorption and improvements in overall calcium nutrition. Additional effects mediated indirectly through enhancements in renal calcitriol synthesis as intestinal phosphorus absorption diminishes and through phosphorus-dependent changes in PTH mRNA stability also probably contribute. ^{[231] [232] [233]}

Vitamin D Sterols

Small oral doses of calcitriol are useful for enhancing intestinal calcium absorption and for preventing hypocalcemia among patients with CKD stages, 3 or 4. Daily doses of 0.25 to 0.5 mg have generally proven to be safe.^[94] Apart from serving to maintain serum calcium concentrations within the normal range, calcitriol therapy diminishes pre-pro-PTH gene expression and lowers plasma PTH levels among patients who already have biochemical evidence of SHPT. For reasons of safety, serum calcium concentrations should be measured regularly during treatment with calcitriol in patients with CKD stages, 3 or 4, and hypercalcemia is to be avoided. Calcium excretion in the urine should be monitored periodically, particularly in those who are also ingesting calcium-containing medications, to prevent hypercalciuria.

Treatment with oral doses of doxercalciferol or paricalcitol represent safe and effective alternatives to calcitriol therapy among patients with SHPT due to CKD, stages 3 and 4. ^{[97] [98]} The therapeutic use of these two compounds lowers plasma PTH levels, whereas serum calcium and phosphorus concentrations generally remain unchanged. Calcium excretion in the urine increases only modestly. ^{[97] [98]}

Although most pronounced among patients with CKD, stage 5, who are treated with dialysis, vascular calcification is common at earlier stages of CKD.^[234] Diabetes is the predominant risk factor. Based upon the reported relationships between abnormalities in calcium and phosphorus metabolism and the risk of vascular calcification among patients undergoing dialysis regularly, ^{[11] [172]} concerns have arisen that disorders of calcium and phosphorus metabolism, including SHPT, also contribute to the development of vascular calcification among patients with CKD, stage 2 through 4. In this context, clinicians may be disinclined to use either calcium-containing compounds or vitamin D sterols to treat SHPT in an effort to diminish these risks.^[200]

It is likely that atherosclerosis and diabetes rather than alterations in mineral metabolism account for the greater prevalence of vascular calcification among patients with mild to moderate CKD as compared with the general population.^[234] Serum phosphorus levels are elevated infrequently and serum calcium concentrations are normal or reduced in most patients with CKD, stage 2 through 4. In particular, there is little evidence to suggest ongoing phosphorus retention among patients whose glomerular filtration rates exceed 20 to 25 mL/min.^[231] As such, the biochemical disturbances in mineral metabolism that characterize patients undergoing dialysis regularly are largely absent in those with mild to moderate CKD.

Several reports indicate, however, that serum phosphorus levels are positively associated with mortality risk among patients with CKD who do not require dialysis. ^{[14] [15]} Whether serum phosphorus concentrations simply serve as a surrogate marker for the severity of CKD and thus explain these relationships is uncertain. Additional work is required to further clarify this important issue.

Vitamin D Nutrition

Apart from the use of vitamin D sterols to treat SHPT and to control plasma PTH levels, biochemical screening should be done periodically to identify patients with inadequate vitamin D nutrition or overt vitamin D efficiency by measuring the serum levels of 25-hydroxyvitamin D. Vitamin D deficiency is associated with biochemical evidence of SHPT in the general population, and it may also contribute to SHPT among patients with mild to moderate CKD, although this issue has not been examined carefully.^[97] Either ergocalciferol or cholecalciferol can be given to restore vitamin D nutrition by raising serum 25-hydroxyvitamin D levels to values of 30ng/mL or greater, but ongoing biochemical surveillance is required to monitor the adequacy of vitamin D nutrition among patients CKD.^[19]

Calcimimetic Agents

Calcimimetic agents such as cinacalcet are not approved currently for treating SHPT among patients with CKD who do not require treatment with dialysis. Experience with this therapeutic approach is quite limited among patients with CKD, stages 3 and 4. Treatment with cinacalcet lowers plasma PTH levels effectively, but serum phosphorus concentrations increase modestly.^[235] Although serum phosphorus levels generally remain within the normal range, values become elevated in some patients, particularly those with more advanced CKD. As such, concurrent treatment with phosphate-binding compounds may be required to control serum phosphorus levels adequately. Serum calcium levels also decrease during treatment with cinacalcet among patients with CKD, stages 3 and 4, and this biochemical change may limit the doses that can be used safely to control SHPT.^[235] The effectiveness of daily doses smaller than 30 mg has not been evaluated in patients with CKD, stages 3 and 4.

Further studies are required to determine the safety and efficacy of cinacalcet for managing SHPT among patients with CKD, stages 2 to 4. The effect of cinacalcet to retard parathyroid gland hyperplasia in experimental models of SHPT due to CKD indicates, however, that the clinical use of this therapeutic agent among patients with mild to moderate CKD has the potential to modify disease progression.

Chronic Kidney Disease, Stage 5

Phosphate-Binding Agents and Calcium Metabolism

Limiting phosphorus retention and controlling serum phosphorus levels adequately has traditionally been a key component of the clinical management of patients with CKD, stage 5, who are undergoing dialysis regularly. ^{[200] [202]}Virtually all patients who are treated with dialysis regularly require dietary phosphorus restriction and phosphate-binding medications to control serum phosphorus levels and to limit the frequency and severity of episodes of hyperphosphatemia. These interventions are needed whether or not there is biochemical evidence of SHPT. Epidemiologic data demonstrating that elevated serum phosphorus levels are associated with an increase in mortality, primarily from cardiovascular causes, among patients undergoing dialysis regularly further underscore the importance of controlling this biochemical disturbance. ^{[11] [18] [236] [237]} Results from experimental studies in animals and from assessments of vascular smooth muscle cells in vitro provide compelling evidence that phosphorus is a major factor in the calcification of extracellular matrix including elastic collagen in the arterial wall. ^{[5] [238] [239] [240] [241]}

Calcium carbonate, calcium acetate, sevelamer, and lanthanum carbonate are the four phosphate-binding agents currently available for use clinically. Available guidelines suggest that the total amount of elemental calcium used in phosphate-binding regimens be limited to 1500 mg/day.^[19] In part, the recommendation is based upon concerns about the relationship between the use of large oral doses of calcium and the development of soft-tissue and vascular calcification among patients undergoing dialysis regularly. ^{[208] [242]} Smaller amounts or calcium are often insufficient, however, to control serum phosphorus levels adequately. Combined therapy with calcium-containing compounds and calcium-free agents is thus usually required.^[13]

Although data on morbidity and mortality are not yet available, results from one prospective clinical trial indicate that the use of calcium-containing, phosphate-binding agents is associated with worsening vascular calcification among patients undergoing hemodialysis regularly, whereas the use of the calcium-free compound sevelamer is not.^[222] Such findings provide support for limiting the cumulative daily intake of calcium from both dietary and medicinal sources to 2000 mg, as recommended in the K/DOQI guidelines.^[19] The levels of calcium intake that are suitable for patients with CKD who have little or no residual renal function remain uncertain, however, and the amounts required to increase the risk of soft-tissue and vascular calcification are not known. Because vitamin D sterols enhance intestinal calcium absorption, concurrent therapy with vitamin D is likely to modify these risks.

If serum phosphorus levels remain elevated despite the use of up to 1500 mg of elemental calcium per day as phosphate-binding compounds, then calcium-free phosphate-binding agents should be added to the therapeutic regimen. The choice between sevelamer and lanthanum carbonate often rests upon the personal preference of the clinician. Patient tolerance, pill burden, compliance and cost should also be considered.

For patients with evidence of vascular calcification, sevelamer may be advantageous as a calcium-free agent based on clinical data indicating that vascular calcification does not progress during treatment with this particular phosphate-binding agent. ^{[222] [243]} Results from prospective clinical trials to assess the progression of vascular calcification during treatment with lanthanum carbonate as compared with calcium-containing compounds are not available. If plasma PTH levels are controlled adequately with the coordinated use of oral calcium supplements and phosphate-binding agents, additional treatments for SHPT are not required. Serial measurements of plasma PTH should be done to monitor the adequacy of disease control.

Among patients who use sevelamer or lanthanum carbonate exclusively to control serum phosphorus levels, the dietary intake of calcium from phosphorus-restricted diets may not be sufficient for nutritional needs. Modest supplemental oral doses of calcium or the use of small doses of calcium-containing, phosphate-binding agents may be required in such patients. Such measures should be implemented for patients with hypocalcemia.

Vitamin D Sterols

Correcting hyperphosphatemia with phosphate-binding agents may lower plasma PTH levels modestly among patients with SHPT, but this does not represent a definitive and reliable pharmacologic intervention for controlling the disorder. Vitamin D sterols that target the VDR and calcimimetic agents that target the CaSR are the two pharmacologic interventions currently available that act specifically to modify parathyroid gland function and to lower plasma PTH levels definitively. Either or both can be used to treat SHPT when plasma PTH levels remain elevated after measures have been implemented to control serum phosphorus levels and to optimize calcium nutrition.

Calcitriol, paricalcitol, doxercalciferol and maxacalcitol have all been shown to lower plasma PTH levels in patients with SHPT due to CKD, stage 5. Among patients undergoing hemodialysis regularly, intravenous doses given thrice-weekly during each dialysis session are used most often. Treatment with daily oral doses of calcitriol is done infrequently in the United States, but it is not uncommon elsewhere. Studies to assess the efficacy of daily oral doses of either paricalcitol or doxercalciferol among hemodialysis patients with SHPT have not been reported. There is only limited evidence that large intermittent intravenous doses of vitamin D sterols are more effective than oral calcitriol therapy for managing SHPT among patients with CKD, stage 5. ^{[116] [117] [118] [122]}

Parenteral vitamin D therapy is generally begun using small initial doses if serum calcium and phosphorus levels are not elevated. Doses are raised subsequently in increments to lower plasma PTH levels. The use of larger initial doses of paricalcitol has been suggested to be a safe alternative among patients with severe disease and markedly elevated plasma PTH levels.^[244] Caution is warranted, however, because of the potential for raising serum calcium and phosphorus levels when treatment is begun.

Among patients who respond favorably to treatment, plasma PTH levels decline progressively over several months. The primary therapeutic objective is to maintain plasma PTH levels within a range of 150 to 300pg/mL. Lowering plasma PTH levels further increases the likelihood of episodes of hypercalcemia, and it can lead to the development of adynamic renal osteodystrophy.^[149]

The doses of vitamin D sterols that can be given safely to control plasma PTH levels are determined by monitoring serum calcium and phosphorus concentrations during therapy. Values often increase during treatment, and these biochemical changes mandate that the dose of vitamin D be reduced or that treatment be withheld temporarily to limit the risk of extraosseous calcification. The K/DOQI guidelines advise against initiating treatment with vitamin D sterols or continuing vitamin D therapy when serum calcium levels exceed 9.5 to 10.0 mg/dL or when serum phosphorus levels exceed 5.5 mg/mL.^[19] Although definitive evidence to support these recommendations is not available, data from epidemiologic studies of patients undergoing hemodialysis regularly indicate that mortality risk increases progressively as serum calcium and phosphorus levels rise above these values. ^{[11] [172]}

Treatment with cinacalcet should be considered as an alternative to vitamin D sterols for lowering plasma PTH levels among patients with SHPT who have recurrent episodes of hypercalcemia or hyperphosphatemia either before or during treatment with vitamin D. The therapeutic use of any vitamin D sterol is likely to increase the frequency and severity of these biochemical disturbances.

Because vitamin D sterols can increase serum calcium concentrations, their use therapeutically can be helpful in correcting hypocalcemia in some patients with CKD, stage 5, thus removing a potent stimulus for PTH secretion. Calcitriol may be more effective for this purpose than other vitamin D sterols that are purported to be less potent than calcitriol in raising serum calcium concentrations, but evidence from clinical trials to support such differences among the various vitamin D sterols is limited. Treatment with vitamin D sterols rather than cinacalcet is recommended for patients with hypocalcemia owing to the calcium-lowering effect of calcimimetic agents.^[155]

There is considerable concern about the relationship between disorders of calcium and phosphorus metabolism and adverse clinical outcomes among patients with CKD. Because treatment with vitamin D may aggravate these disturbances, the use of vitamin D sterols should be limited or avoided altogether when serum calcium and phosphorus levels are not controlled adequately.^[19] Nevertheless, results from two retrospective studies suggest that treatment with paricalcitol favorably influences survival among patients undergoing hemodialysis regularly. ^{[245] [246]} In one report, mortality rates after 3 years of follow-up were lower among patients given paricalcitol than in patients managed clinically with calcitriol.^[245] In the other report, survival after 2 years was greater among patients who received paricalcitol during the first 12 months of treatment with hemodialysis as compared with those who received no vitamin D during this interval.^[246] In multivariate analyses, the beneficial effect of treatment with paricalcitol on survival persisted without regard to the serum levels of calcium or phosphorus.

Such findings are notable and potentially important, but they are limited by the retrospective nature of the data reported. Prospective clinical trials are needed to confirm these preliminary observations.^[247]

Downward adjustments to the concentration of calcium in dialysate have been used to permit treatment with larger oral doses of calcium-containing compounds to control serum phosphorus levels or to allow the continued use of vitamin D sterols to manage SHPT among patients with persistently elevated serum calcium concentrations. ^{[248] [249]} There is little evidence to support these measures. Dialysate calcium levels below the normal physiologic concentration of ionized calcium in blood will provoke PTH secretion during each dialysis session and thus provide ongoing and recurrent stimuli for PTH secretion and parathyroid gland hyperplasia. As such, the use of dialysis solutions containing calcium concentrations lower than 2.5 mEg/L, or 1.25 mmol/L, may aggravate SHPT among patients with CKD, stage 5.^[250]

Vitamin D Nutrition

If 25-hydroxyvitamin D levels are reduced, treatment with ergocalciferol or cholecalciferol should be considered to restore adequate vitamin D nutrition even among patients undergoing dialysis regularly. As noted previously, 25-dihydroxyvitamin D is the substrate for 1-alpha-hydroxylase enzymes that mediate calcitriol production locally in tissues other than kidney. The suggestion to replenish vitamin D stores is based on the high prevalence of nutritional vitamin D deficiency among patients with CKD^[48] and the unproven possibility that maintaining adequate vitamin D nutrition will support the tissue-specific synthesis of 1,25-dihydroxyvitamin D in extrarenal tissues. Such an approach would not be expected to enhance renal calcitriol synthesis substantially or to raise serum calcitriol levels, and it would not be undertaken for this purpose. There is no evidence currently to support a salutary benefit of nutritional vitamin D repletion among patients with CKD, stage 5, but studies to address this issue specifically and the safety of such an approach have not been done.

Calcimimetic Agents

Cinacalcet effectively lowers plasma PTH levels among patients with SHPT due to CKD, stage 5, by activating the CaSR and inhibiting PTH secretion. In contrast to treatment with vitamin D sterols, serum calcium concentrations decrease during cinacalcet therapy. Serum phosphorus levels also decline modestly in many patients. Because cinacalcet does not raise serum calcium and phosphorus levels, it can be used therapeutically among patients with SHPT who have persistent or recurrent elevations in these two biochemical parameters. This includes patients who cannot be given vitamin D sterols safely because serum calcium or phosphorus levels exceed values that are acceptable and those who experience recurrent episodes of hypercalcemia or hyperphosphatemia during vitamin D therapy.

Cinacalcet can also be used as a primary intervention for SHPT when pretreatment serum calcium concentrations are normal or elevated. In contrast, treatment with vitamin D sterols would be more suitable as an initial intervention for SHPT among patients with low serum calcium levels. Treatment with vitamin D may correct this biochemical abnormality, whereas the administration of cinacalcet might lower serum calcium concentrations further.

Cinacalcet is available only as an oral medication. It is not available currently as a preparation that can be given intravenously. Treatment is initiated with single daily oral doses of 30 mg without regard to disease severity. Doses are titrated upward at 2- to 4-week intervals in increments of 30 mg to a maximum daily dose of 180 mg to lower plasma PTH levels if serum calcium levels remain within acceptable limits. Decreases in serum calcium concentration in some patients may limit the doses that can be used to control plasma PTH levels.

Although patients with more advanced SHPT may ultimately require larger daily doses of cinacalcet during ongoing treatment, it is imperative to adhere to the recommended dose-titration scheme. The use of initial doses greater than 30 mg may lower serum calcium concentrations abruptly, and symptomatic hypocalcemia can occur. These untoward side effects are avoided when treatment is undertaken using incremental dosage adjustments. Serum calcium levels should be measured, however, after the first week of treatment to confirm that values have not decreased substantially.

Plasma PTH levels decline progressively during the first 10 to 12 weeks of treatment with cinacalcet as doses are raised incrementally. Serum calcium concentrations also decrease modestly during this interval. The changes are greatest during the first several weeks of treatment, but values do not decline further as treatment is continued among patients receiving constant daily doses. Sustained reductions in serum phosphorus levels are common.

Treatment with cinacalcet may be sufficient alone to lower plasma PTH levels to the therapeutic target range of 150 to 300pg/mL as recommended generally.^[19] If decreases in serum calcium preclude upward adjustments to the dose of cinacalcet and plasma PTH levels remain elevated, treatment with vitamin D sterols can be added. By inhibiting PTH synthesis, vitamin D sterols will act to further reduce plasma PTH levels and their use may offset the calcium-lowering effect of cinacalcet.

Subsequent adjustments to the doses of cinacalcet and vitamin D to control plasma PTH levels optimally can be made based on repeated measurements of serum calcium and phosphorus concentrations. If values are elevated, thus precluding the use of larger doses of vitamin D sterols, the dose of cinacalcet can be adjusted upward to achieve further reduction in plasma PTH levels. In contrast, if serum calcium levels are low, increasing the dose of cinacalcet may aggravate this biochemical change. Under these circumstances, increasing the dose of vitamin D sterols may achieve additional reductions in plasma PTH levels while concurrently raising serum calcium concentrations.

The opposing effects of cinacalcet and vitamin D sterols on serum calcium and phosphorus levels makes it possible to use these two agents in a coordinated and complimentary fashion to lower plasma PTH levels while concurrently maintaining serum calcium and phosphorus concentrations within the ranges advocated by the K/DOQI guidelines.^[175]

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