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Treatment

CASE 28-3, QUESTION 2: What are the goals of therapy for W.K.’s calcium, phosphorus, and PTH

abnormalities? What options are available to treat these disorders?

The management objectives for W.K. are to (a) manage serum calcium and

phosphorus concentrations, (b) prevent or manage SHPT, and (c) restore normal

skeletal development without inducing adynamic bone disease (or low bone

turnover). These goals are best achieved with dietary phosphorus restriction,

appropriate use of phosphate-binding agents, vitamin D therapy, calcimimetics, and

dialysis.

DIETARY RESTRICTION OF PHOSPHORUS

In general, serum phosphorus should be lowered toward near-normal levels. The

KDIGO recommends normal levels for all stages of CKD. Dietary phosphorus

restriction can prevent hyperphosphatemia and maintain target phosphorus

concentrations. Dietary phosphorus should not exceed 800 to 1,000 mg/day.

92

Predominate sources of phosphorus are protein-rich foods, which presents a

challenge in tailoring a diet that lowers dietary phosphorus intake while providing

adequate nutrition. However, efforts should be made to distinguish between organic

(e.g., plant seeds, nuts, legumes, and meats) and inorganic phosphorus (e.g.,

preservatives and additive salts found in processed foods) sources. Inorganic

phosphorus sources are absorbed to a greater extent than organic phosphorus (90%

vs. 50%, respectively) and should be minimized in the diet.

133 Dark carbonated

beverages are a common culprit for elevated phosphorus levels; their consumption

should be discouraged, and the beverages should be removed from vending machines

in dialysis clinics. Additionally, the type of organic phosphorus sources, plant versus

meat, has varying effects with plant sources associated with lower serum phosphorus

levels and decreased FGF23 levels. Although phosphorus is removed to some extent

by dialysis, neither conventional HD nor PD removes adequate amounts to warrant

complete liberalization of phosphorus in the diet. Nocturnal HD is an exception

where patients may require phosphate supplements because of the prolonged dialysis

duration. Regular dietary counseling by a kidney dietitian specialist is necessary to

reinforce the importance of phosphorus restriction and other dietary

recommendations.

PHOSPHATE-BINDING AGENTS

A significant reduction in serum phosphorus is difficult to achieve with dietary

intervention alone, particularly in patients with more advanced kidney disease

(eGFR <30 mL/minute/1.73 m2

). For these patients, phosphate-binding agents used in

conjunction with dietary restriction are necessary. Phosphate-binding agents limit

phosphorus absorption from the GI tract by binding with the phosphorus present from

dietary sources. Therefore, these agents must be administered with meals. Available

binders include products that contain calcium, iron, lanthanum, aluminum, or

magnesium cations or the polymer-based agent, sevelamer.

Calcium-Containing Preparations

Calcium-containing preparations, especially calcium carbonate and calcium acetate,

are frequently used to prevent hyperphosphatemia in patients with kidney disease.

The many preparations available vary in their calcium content (Table 28-10).

Correction of hypocalcemia is an added beneficial effect of the calcium-containing

preparations; however, a risk exists of hypercalcemia and cardiac calcification

associated with the prolonged use of these agents.

134 Additionally, the higher

bioavailable calcium in calcium carbonate may lead to positive calcium balance.

135

Calcium citrate is a calcium salt with a phosphate-binding capacity similar to that of

calcium carbonate; however, because it also increases aluminum absorption from the

GI tract, its use is not recommended in patients with kidney disease.

Simultaneous administration of vitamin D preparations and calcium also increases

the risk of hypercalcemia. A corrected serum calcium should be determined before

therapy is started and at regular intervals thereafter.

Many clinicians often correct calcium levels for low albumin. Although this

practice is still very common, new Medicare Quality Improvements will be based on

uncorrected total serum calcium levels. Calculating corrected calcium adjusts for the

change in the ratio of free (unbound) versus protein-bound calcium owing to reduced

serum albumin concentrations (Eq. 28-7).

Calcific uremic arteriolopathy (CUA) or calciphylaxis, is characterized by

calcification of the arterioles and small arteries with intimal proliferation and

endovascular fibrosis. CUA and manifests visually as necrosis of the skin and is most

frequently seen in dialysis patients, affecting up to 5% of patients. Calcium-based

phosphate binders are one of the triggering factors associated with the development

of CUA.

If the patient experiences hypercalcemia or evidence of advance calcification, the

patient should be switched to a non–calcium-based phosphate binder. Alternatives

include sevelamer and cations, such as lanthanum carbonate or magnesium

preparations. For patients requiring dialysis, reducing the calcium concentration of

the dialysate bath may decrease the risk of hypercalcemia. Although avoiding

hypercalcemia should reduce the risk of cardiac calcification, calcifications still can

occur because of other contributing factors in the CKD population (e.g.,

hyperphosphatemia).

Nausea, diarrhea, and constipation are other side effects of calcium-containing

products. Because calcium-containing phosphate binders may interact with other

drugs, the timing of their administration relative to other agents must be considered.

Fluoroquinolones and oral iron, for example, should be taken at least 1 or 2 hours

before calcium-containing phosphate binders. Importantly, if the calcium products are

being used as supplementation to treat hypocalcemia or osteoporosis, they should be

taken between meals to enhance intestinal absorption. This is in contrast to their

administration with meals if they are being used as phosphate binders. Starting doses

of common calcium-containing phosphate binders are listed in Table 28-10.

Sevelamer

Sevelamer hydrochloride (Renagel) or carbonate (Renvela) is a nonabsorbed,

polymer-based product that binds phosphorus in the GI tract.

136,137 The benefit of

lowering phosphorus without significantly affecting serum calcium has led to the

increased use of sevelamer in patients with CKD. Sevelamer also lowers LDL and

total serum cholesterol, a benefit considering the increased risk of cardiovascular

events in this population.

92

Sevelamer has a potential benefit of attenuating the progression of coronary

calcification, which may be related to its LDL and total serum cholesterol-lowering

effects and a benefit from reduced calcium loading. The actual benefit of sevelamer

on mortality is controversial. The post hoc analysis of the Renagel in New Dialysis

(RIND) trial showed a survival advantage with sevelamer compared with calcium

acetate; however, the Dialysis Clinical Outcomes Revisited (DCOR) trial failed to

show a difference in mortality between the two agents.

138 One explanation for the

disparity in results may be the difference in the population of patients on HD between

the two trials. The RIND trial included incident patients on HD, whereas the DCOR

trial included prevalent HD patients who likely would have advanced CVD.

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p. 620

Table 28-10

Available Phosphate Binders

Agent

Availability (Pill

Burden) Comments Adverse Effects and Warnings

Aluminum-Based Binder

Aluminum hydroxide 320 mg/5 mL

suspension

OTC Constipation and sodium overload

Aluminum toxicity: CNS, anemia,

and bone disease

Warnings: perforation, fecal

impaction, ileus

Calcium-Based Binders

Calcium acetate 667 mg caplets

(3–12 caplets)

667 mg/5 mL

(15–20 mL with meal)

Oralsolution

associated with higher

diarrhea risk

N/V/D; hypercalcemia; vascular

calcification; oralsolution associated

with greater diarrhea

Calcium carbonate 500–1,250 mg tablets OTC N/V/D; hypercalcemia; vascular

(3–6 tablets) calcification

Iron-Based Agents

Ferric citrate 210 mg ferric iron

tablet

(6–12 tablets)

210 mg of ferric iron =

1 g ferric citrate

N/V/D; discolored feces; iron

overload

Precautions: gastric/hepatic

disorders;

CI: hemochromatosis

Sucroferric

oxyhydroxide

500 mg chewable

tablet

(3–6 tablets)

500 mg ferric iron =

2,500 mg sucroferric

oxyhydroxide

N/D; discolored feces; iron overload

Precautions: gastric/hepatic

disorders; hemochromatosis

Lanthanum-Based Binder

Lanthanum 500, 750, and 1,000 mg

chewable tablets

(3–6 tablets)

Chewed and crushed

have similar efficacy

Accumulation in bone, brain, and

liver; visible on abdominal X-ray;

hypercalcemia

CI: bowel obstruction, ileus, and

fecal impaction

Magnesium-Based Binder

Magnesium hydroxide 311 mg tablets

(1–6 tablets)

OTC; impair iron

absorption

Hypermagnesemia; diarrhea very

common

Resin Binders

Sevelamer carbonate 800 mg caplet

(3–12 caplets)

0.8 g/2.4 g powder

packets

Reduces low-density

lipoprotein cholesterol

N/V/D; hypercalcemia

CI: bowel obstruction

Warnings: perforation, fecal

impaction

Sevelamer

hydrochloride

400, 800 mg caplets

1–2 tablets TID

(6–12 caplets)

Reduces low-density

lipoprotein cholesterol

N/V/D; hypercalcemia

CI: bowel obstruction

Warnings: perforation, fecal

impaction; risk of metabolic acidosis

CI, contraindications; N/V/D, nausea, vomiting, diarrhea.

Sevelamer hydrochloride is available as 400- and 800-mg tablets. Sevelamer

carbonate is available as 800-mg tablets and 0.8-g powder packets. The phosphorusbinding capacity remains equipotent between the two formulations. The starting dose

is variable and depends on the baseline serum phosphorus concentration (800 mg

TID with meals if serum phosphorus is <7.5 mg/dL; 1,600 mg TID with meals if

serum phosphorus is >7.5 mg/dL).

136,137 Gradual adjustments can be made at 2-week

intervals, based on serum phosphorus levels. Dosing guidelines for sevelamer are

also available for patients being converted from calcium acetate. On the basis of

studies showing similar reductions in serum phosphorus, 800 mg of sevelamer is

considered equivalent to 667 mg of calcium acetate (169 mg of elemental calcium).

137

The administration of sevelamer hydrochloride to patients on HD is associated

with a lowering of serum bicarbonate; this effect should be taken into account when

using this agent. Sevelamer carbonate avoids the metabolic acidosis seen with the

hydrochloride formulation and raises the serum bicarbonate level.

139 Adverse reports

of fecal impaction, ileus, intestinal obstruction, and perforation should caution the

use in patients with GI disease. The current prescribing information recommends

administering sevelamer 1 hour before or 3 hours after administration of other agents

with narrow therapeutic indices.

136,137

Lanthanum Carbonate

Lanthanum carbonate (Fosrenol) is a noncalcium, nonaluminum phosphate binder

preparation. When ingested, it dissociates into a trivalent cation with similar binding

capacity as aluminum salts. Lanthanum also has been found to be as effective and

tolerable as standard treatment. Both calcium and iPTH were lower in the lanthanum

group.

140 Lanthanum is mainly excreted via the biliary route, with minimal kidney

elimination.

p. 620

p. 621

Studies have evaluated the deposition and toxicity of lanthanum in the bone, liver,

and brain due to concerns of lanthanum accumulation. Although lanthanum

accumulates in lysosomes in the liver, this has not been correlated with increased

liver enzymes or hepatobiliary adverse events in patients receiving lanthanum for up

to 6 years.

141 This is likely an excretory process through the biliary tract similar to

that for iron and copper. A prospective trial of patients on HD receiving lanthanum

for 1 year found minimal deposition of lanthanum within the bone and less likelihood

of adynamic bone histology compared with patients receiving calcium carbonate.

142

During a 2-year period, patients receiving lanthanum were not found to accelerate the

natural deterioration in cognitive function seen in patients on HD.

143

Lanthanum is supplied as chewable tablets for oral administration in four

strengths: 250, 500, 750, and 1,000 mg. The recommended initial total daily dose is

750 to 1,500 mg given with meals, and dosage titration up to a maximal dosage of

3,000 mg daily based on serum phosphate levels. Lanthanum retains the same

phosphorus-binding capabilities irrespective of whether it is chewed or crushed into

powder.

144 Drug interactions with lanthanum include a reduction in the

bioavailability of ciprofloxacin (approximate 50% reduction) and levothyroxine. The

most frequent adverse events reported in clinical trials are nausea and vomiting.

145

Iron-Based Phosphate Binders

Sucroferric oxyhydroxide and ferric citrate are iron-based phosphate binders with

proven efficacy at reducing serum phosphate levels in hemodialysis patients. The

newer iron-based binder ferric citrate has the advantage of providing supplemental

iron. Early studies of ferric citrate demonstrate a reduction in IV iron and EPOstimulating agent use.

146 However, sucroferric oxyhydroxide as a chewable tablet is

not systemically absorbed, thus not affecting anemia management.

147

Other Phosphate Binders

Aluminum preparations are very potent dietary phosphorus binders. Although these

products were once used as first-line agents to decrease phosphorus, aluminum

accumulation and toxicities in patients with CKD have restricted their use. Aluminum

toxicity occurs in dialysis patients because absorbed aluminum is not removed by the

diseased kidney and enters various tissues where it binds to tissue and plasma

proteins. Aluminum accumulation in the bone, brain, and other organs leads to

toxicities such as osteomalacia (aluminum-related bone disease), microcytic anemia,

and a fatal neurologic syndrome referred to as dialysis encephalopathy.

91 Treatment

of aluminum toxicity requires chelation with deferoxamine. Aluminum-containing

agents should only be considered on a short-term basis (up to 4 weeks) for patients

with a severely elevated phosphorus

91

; however, high-dose lanthanum may generally

be preferred in these situations. Sucralfate, used primarily for the treatment of ulcers,

also contains aluminum and should be used cautiously in patients with kidney

disease.

Magnesium agents (magnesium hydroxide, magnesium carbonate) may be

beneficial, but as with aluminum, their use should be limited because at the high

doses required to control serum phosphorus concentrations, severe diarrhea and

hypermagnesemia invariably result. Magnesium may be considered in patients whose

serum phosphorus concentrations cannot be controlled adequately by other

phosphate-binding agents. In this instance, a magnesium-containing phosphate binder

may be added in conjunction with a reduction in the dialysate magnesium

concentration (in the dialysis population). These agents should not be considered

first-line therapy for control of phosphorus, and careful monitoring of magnesium is

warranted if therapy is started.

More aggressive control of W.K.’s serum phosphorus is needed to lower serum

phosphorus toward normal levels. Currently, W.K. is taking a calcium-based

phosphate binder. Although presumably much of this calcium will be bound to

phosphorus in the GI tract, a potential exists for calcium absorption. Furthermore, her

serum calcium levels are in the upper range of normal not corrected. Sevelamer

should be started to limit her calcium exposure and decrease her phosphorus levels.

The recommended starting dose is 800 mg TID with meals, titrated based on followup phosphorus values. Adjustments should also be considered in conjunction with

vitamin D therapy (see Vitamin D section). W.K. should be instructed to take her

phosphate binder with meals. This regimen should be implemented in conjunction

with a restricted-phosphorus diet. Regular reinforcement of the importance of

compliance is necessary because nonadherence with prescribed dietary phosphorus

restriction and drug therapy is one of the most significant factors associated with

treatment failure. Use of a low-calcium dialysate may also help decrease her risk of

hypercalcemia.

VITAMIN D

Nutritional Vitamin D

Nutritional vitamin D (NVD) occurs naturally as ergocalciferol (vitamin D2

)

obtained from dietary sources and as cholecalciferol (vitamin D3

) obtained from

dietary sources and activated in the skin by sunlight in mammals, both of which are

inactive precursors of active forms of vitamin D. An intermediate activation step

(25-hydroxylation) occurs in the liver to produce 25-hydroxy vitamin D (25-

hydroxycalciferol), which is also relatively inactive (Fig. 28-2). Final activation (1-

hydroxylation) occurs in the kidney, yielding calcitriol (l,25-

dihydroxycholecalciferol), the active form of vitamin D. Thus, the response to

vitamins D2 and D3

in patients with compromised kidney function can vary,

depending on the degree of kidney dysfunction and the ability of the kidney to

metabolize 25-hydroxyvitamin D to calcitriol. Decreased levels of 25-

hydroxyvitamin D occur in the early stages of CKD, reducing substrate for producing

calcitriol.

91 Altered vitamin D metabolism that occurs in this population warrants

measurement of 25-hydroxyvitamin D and supplementation with NVD. Oral therapy

with active vitamin D (oral calcitriol) or an analog (oral doxercalciferol) is likely

warranted only when PTH remains elevated despite normal 25-hydroxyvitamin D

levels.

91 As the final, active metabolite of vitamin D, calcitriol (or another activated

form of vitamin D) is usually required in patients with more severe kidney disease

(CKD 4–5).

Several small studies have shown that the benefits of NVD administration extend

beyond bone and mineral metabolism. Reduction in ESA doses, improved glycemic

control, reduced activated vitamin D administration, and inflammation modulation

are benefits observed from NVD supplementation in dialysis patients.

148,149 Although

some effects have been repeated in different studies, randomized control trials are

needed to confirm these benefits.

Vitamin D Receptor Agonist

Calcitriol

Administration of vitamin D receptor agonist (VDRA), active vitamin D, in

conjunction with control of serum phosphorus and calcium, is necessary in many

patients with CKD to manage CKD-MBD. Calcitriol interacts with the vitamin D

receptor (VDR) located in the parathyroid gland, intestines, bone, and kidney. It is

thought to decrease PTH messenger RNA, resulting in decreased PTH secretion. In

addition, calcitriol stimulates calcium absorption from the GI tract to correct

hypocalcemia and prevent SHPT. In order to avoid hypercalcemia, the lowest

effective dose should be used, and the patient’s serum calcium should be monitored

at least every 2 weeks for 1 month and then monthly thereafter. Furthermore,

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p. 622

control of serum phosphorus is critical before calcitriol is initiated, as vitamin D

increases GI phosphorus absorption.

Calcitriol is available as an oral formulation (Rocaltrol) or IV formulation

(Calcijex). Administration of calcitriol by either the oral or IV route may be based on

conventional dosing (usually 0.25–0.5 mcg/day) or pulse dosing (intermittent dosing

of 0.5–2.0 mcg 2–3 times/week). Higher doses (e.g., 4 mcg 3 times/week) are

generally required to reduce PTH secretion in more severe SHPT (PTH >1,000

pg/mL). Daily dosing of 0.25 to 0.5 mcg may be preferred in patients with

hypocalcemia because this regimen primarily works to stimulate calcium absorption

from the GI tract. Intermittent dosing of IV calcitriol is routine in the HD population

because administration is coordinated with dialysis. In contrast, oral dosing is more

convenient in patients with CKD who are not having dialysis and the PD population.

Intact PTH and serum calcium concentrations are used to determine starting doses

and dosing adjustments for calcitriol. Changes in Medicare have resulted in more

outpatient hemodialysis units utilizing oral activated vitamin D therapy.