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Radiographic studies show calcium-phosphate deposits in joints and/or cardiovascular system

Bone biopsy of the iliac crest Nonpharmacologic Therapy

The first-line treatment for the management of hyperphosphatemia is dietary phosphorus restriction to 800 to 1,000 mg/day in patients with stage 3 CKD or higher who have phosphorus levels at the upper limit of the normal range or elevated iPTH levels.56 Foods high in phosphorus are also high in protein, which can make it difficult to restrict phosphorus intake while maintaining adequate protein intake to avoid malnutrition. Hemodialysis and peritoneal dialysis can remove up to 2 to 3 g of phosphorus per week. However, this is insufficient to control hyperphosphatemia, and pharma-cologic therapy is necessary in addition to dialysis treatment.

Other nonpharmacologic strategies to manage sHPT and BMMD in patients with CKD include restriction of aluminum exposure and parathyroidectomy. Ingestion of aluminum-containing antacids and other aluminum-containing products should be avoided in patients with stage 4 CKD or higher (GFR less than 30 mL/min/1.73 m ) because of the risk of aluminum toxicity and potential uptake into the bone. Purification techniques for dialysate solutions also minimize the risk of exposure to aluminum.

Parathyroidectomy is a treatment of last resort for sHPT, but should be con sidered in patients with persistently elevated iPTH levels above 800 pg/mL (800 ng/L) that is refractory to medical therapy to lower serum calcium and/or phosphorus levels.56 A

portion or all of the parathyroid tissue may be removed, and in some cases a portion of the parathyroid tissue may be transplanted into another site, usually the forearm. Bone turnover can be disrupted in patients undergoing parathyroidectomy whereby bone production outweighs bone resorption. The syndrome, known as "hungry bone syndrome," is characterized by excessive uptake of calcium, phosphorus, and magnesium for bone production, leading to hypocalcemia, hypophosphatemia, and hypomag-nesemia. Serum ionized calcium levels should be monitored frequently (every 4-6 hours for the first 48-72 hours) in patients receiving a parathyroidectomy. Calcium supplementation is usually necessary, administered IV initially, then orally (with vitamin D supplementation) once normal calcium levels are attained for several weeks to months after the procedure.

Pharmacologic Therapy

Phosphate-Binding Agents. When serum phosphorus levels cannot be controlled by restriction of dietary intake, phosphate-binding agents are used to bind dietary phosphate in the GI tract to form an insoluble complex that is excreted in the feces. Phosphorus absorption is decreased, thereby decreasing serum phosphorus levels. The drugs used for binding dietary phosphate are listed in Table 26-6. These agents should be administered with each meal and can be tailored to the amount of phosphorus that is typically ingested during each meal. For example, patients can take a smaller dose with smaller meals or snacks, and a larger dose with larger meals.

Table 26-5 Target Levels for Calcium, Phosphorus, Ca-P, and Intact PTH

Parameter

Stag* î CKD

Slags- 4 CKD

StS CKD

CCarHDMf

'Moimar

"Nornur

S 4-9.5 nia/tIL U.I-2 Î7 mmol/ll

calcium

PIlll'flhllHIlS

7.7 ^AimpAJl oup/ 1,49 rtinyj|/| 1

i.i 4£mgtfL#u87-i.49mnBVt3

îi-i.ï I.VS mmgl/I t

Ca-P pfttJuct

Less than Si mg-TdL- (4.44 mmotVLO

Lpm 1tun 55 mg ,'tlL ÎM4 mmol /L'l

L«i Ihûn 5S mg /dL :4.44 nuTtol VL )

Inrirr PTH

3i-JQ pgrtnl £ WD ncyi or 17-75

JD-110 pg/mL (JQ-llOngrt or 75-

IM-lOOfxynnl Oin-^DD i-iq,'! of

pmol/LJ

114 pmol/L)

16-12 pmoVL)

Ca-I^ cakium-phoiphofut product; CKD, chronic Sidney dtsejii; PTH peraltynoid hoimone.

Ca-I^ cakium-phoiphofut product; CKD, chronic Sidney dtsejii; PTH peraltynoid hoimone.

Calcium-based phosphate binders, including calcium carbonate and calcium acetate, are effective in decreasing serum phosphate levels, as well as in increasing serum calcium levels. Calcium acetate binds more phosphorus than the carbonate salt, making it a more potent agent for binding dietary phosphate. Calcium citrate is usually not used as a phosphate-binding agent because the citrate salt can increase aluminum absorption. The calcium-containing phosphate binders also aid in the correction of metabolic acidosis, another complication of kidney failure. Caution should be used with these agents if serum calcium levels are near the upper end of the normal range or are elevated because of the risk of increasing the Ca-P product and potentiating vascular and soft tissue calcifications. The dose of calcium-based phosphate binders should not provide more than 1,500 mg of elemental calcium per day, and the total elemental calcium intake per day should not exceed 2,000 mg, including medication and dietary intake.56 The most common adverse effects of calcium-containing phosphate binders are constipation and hypercalcemia.

Aluminum- and magnesium-containing phosphate-binding agents are not recommended for chronic use in patients with CKD to minimize the risk of aluminum and magnesium accumulation. Aluminum-containing agents may be used for a short course of therapy (less than 4 weeks) if phosphorus levels are significantly elevated greater than 7 mg/dL (2.26 mmol/L), but should be replaced by other phosphate-binding agents after no more than 4 weeks. Excessive aluminum levels lead to aluminum intoxication, causing neurotoxicity that can manifest as encephalopathy or dementia. Other consequences of aluminum intoxication include anemia and bone disease as aluminum is taken up in place of iron in RBCs and calcium in skeletal bones. In addition to the risk of magnesium accumulation, the use of magnesium-containing agents is also limited by the GI side effects, primarily diarrhea.

Phosphate-binding agents that do not contain calcium, magnesium, or aluminum include sevelamer hydrochloride, sevelamer carbonate, and lanthanum carbonate. These agents are particularly useful in patients with hyperphosphatemia who have elevated serum calcium levels or who have vascular or soft tissue calcifications. Sevelamer is a cationic polymer that is not systemically absorbed and binds to phosphate in the GI tract, and prevents absorption and promotes excretion of phosphate through the GI tract via the feces. Sevelamer has an added benefit of reducing LDL-C by up to 30% and increasing HDL-C levels.56 The most common side effects of sevelamer are GI complaints, including nausea, constipation, and diarrhea. The cost of sevelamer is significantly higher compared to calcium-containing phosphate binders, which often makes sevelamer a second-line agent for controlling phosphorus levels. However, recent studies have demonstrated that sevelamer decreases mortality in patients receiving hemodialysis compared to calcium-containing phosphate binders, primarily by decreasing the occurrence of calcifications in the coronary arteries.5 ,58

Lanthanum is a naturally occurring trivalent rare earth element (atomic number 57). Lanthanum carbonate quickly dissociates in the acidic environment of the stomach, where the lanthanum ion binds to dietary phosphorus, forming an insoluble com pound that is excreted in the feces. Lanthanum has been shown to remove more than 97% of dietary phosphorus from the GI tract.59 Side effects of lanthanum include nausea, peripheral edema, and myalgias.

Vitamin D Therapy. Exogenous vitamin D compounds that mimic the activity of cal-citriol act directly on the parathyroid gland to decrease PTH secretion. This is particularly useful when reduction of serum phosphorus levels does not sufficiently reduce PTH levels. The most active form of vitamin D is calcitriol (1,25-dihydroxyvitamin D). The effects of calcitriol are mediated by upregulation of the vitamin D receptor in the parathyroid gland, which decreases parathyroid gland hyperplasia and PTH synthesis and secretion. However, vitamin D receptor upregulation also occurs in the intestines, which increases calcium and phosphorus absorption, increasing the risk of hypercalcemia and hyperphosphatemia. It is important that serum calcium and phosphorus levels are within the normal range for the stage of CKD and the Ca-P product 2 2 2 2 is less than 55 mg /dL (4.44 mmol /L ) prior to starting calcitriol therapy.

Vitamin D supplementation can be used to lower serum PTH levels in patients with CKD. Ergocalciferol has been shown to be effective in lowering PTH secretion in patients with stage 3 CKD.61 However, as CKD progresses to stages 4 and 5, the kidney loses the ability to produce 1a-hydroxylase, which is responsible for renal activation of vitamin D. In these later stages of CKD, activated vitamin D analogs must be used to decrease PTH secretion. Calcitriol (1,25-dihydroxyvitamin D3) is available commercially as an oral formulation (Rocaltrol by Roche Laboratories, Inc., Nutley, NJ) and an injectable formulation (Calcijex by Abbott Laboratories, North Chicago, IL). This analog has the same biologic activity as endogenous calcitriol. Other vitamin D analogs available in the United States include paricalcitol (19-nor-1,25-dihydroxyvitamin D2, Zemplar by Abbott Laboratories, North Chicago, IL and doxercalciferol (1-a-hydroxyvitamin D2, Hectorol by Genzyme Corp., Cambridge, MA), both of which are also available in oral and injectable formations. Alfa-calcidiol (1-a-hydroxyvitamin D3) is only available outside the United States. Paric-alcitol has less effect on vitamin D receptors in the intestines, decreasing the effects on intestinal calcium and phosphorus absorption, while retaining the effects on parathyroid gland hyperplasia and PTH synthesis and secretion.60 This makes paricalcitol more useful in patients with an elevated Ca-P product. Doxercalciferol, on the other hand, has similar effects as calcitriol on vitamin D receptors in the parathyroid glands and intestines. Like calcitriol, calcium and phosphorus levels and the Ca-P product should be within the normal range for the stage of CKD prior to starting doxercalci-

ferol. Recommendations for vitamin D analog therapy depend on the stage of CKD (Table 26-7).56

Table 26-6 Phosphate-Binding Agents Used in the Treatment of Hyperphosphatemia in CKD

compound

Tradr N.iihll

Compound Content |mgj

Elemental Calcium

Imgi_Starling Dfltt

Comments

Calcium

HO* elemental cak^imf

Calcium jcclalc' (JSib.el^jwnisI talcum)

Se^eljmer Htl ww lamer Carton)»

Tumi

Oscil-SCH CaHrale NiplnoCiti I. PCtUK.il CakiChtw

Phoi-LcN

flonagel, Ptrvtlii

SOft 75$ IjMCt

30a 300,-104 soo

Iff fli-1 9 (elemental i«kpjflff 3 lipriti i rtjy wiili meals

05-1 ykfLTticnlal iali>irrt| 3 liftV^

■sdjy wirh nteils fSOO mg 3 times a day with mcafc

Hirst-bne agent dmolulion ClwiOi Otriiifc-S pHiW'iOlLii-tjinjini] efltert ffty vay from ptoducl to |iroiluc t try lo lnwt cJjily iiiioflie of etemiowl <4kium

AoiHcmmaNrly 59 mg pbQUJho^ tvMjnct fm i g cikium cat borate rirsr-liK' agent icmpji able efficacy[i' «kkim «rt)cw(e wtih em?' half the doio of elfju^ntil i^ViyiYrtlj nw exceed 1,500 rug elemental ejkium imihipci djy ApfMOiimately 45 liig uhwpiiomr;

bound pef I g calcium acelate By peso ifnion only Firit-hne agent loiveti LOL C Mo«e o«pcniivc thus» cjfcium pix**^ pitlwed kipanient; risk ley «ctushEilctal takification Moy requiit.' laigc dos« (o oondol fjl>:j' f>l luiui lew^

It is important to monitor vitamin D therapy aggressively to assure that PTH levels are not oversuppressed. Oversuppression of PTH levels can induce adynamic bone disease, which manifests as decreased osteoblast and osteoclast activity, decreased bone formation, and low bone turnover.

Calcimimetics

Cinacalcet is a calcimimetic that increases the sensitivity of receptors on the parathyroid gland to serum calcium levels to reduce PTH secretion. In addition to lowering PTH levels, cinacalcet has been shown to reduce serum calcium levels by approximately 5% and serum phosphorus levels by 2.6% to 8.4%.62 This makes cinacalcet beneficial to use in patients with elevated PTH levels who have an increased Ca-P product and cannot use vitamin D therapy. Because the effects of cinacalcet on PTH can reduce serum calcium levels and result in hypocalcemia, cinacalcet should not be used if serum calcium levels are below 8.4 mg/dL (2.1 mmol/L). Cincalcet should also be used with caution in patients with seizure disorders because low serum calcium levels can lower the seizure threshold.62

Reversal of Metabolic Acidosis

Studies have demonstrated that reversal of metabolic acidosis can improve bone disease associated with CKD.55 Serum bicarbonate levels should be maintained at 22 mEq/L (22 mmol/L) in patients with bone disease associated with CKD.56 The treatment of metabolic acidosis is described later.

Outcome Evaluation

Monitor serum calcium and phosphorus levels regularly in patients receiving phosphate-binding agents. When initiating therapy, monitor serum levels every 1 to 4 weeks, depending on the severity of hyperphosphatemia. Titrate doses of phosphate binders to achieve the target levels of serum calcium and phosphorus and the Ca-P product (Table 26-5). Once target levels are achieved, monitor serum calcium and phosphorus levels every 1 to 3 months. Monitor intact PTH levels monthly while initiating vitamin D therapy, then every 3 months once stable iPTH levels are achieved. When starting or increasing the dose of cinacalcet, monitor serum calcium and phosphorus levels within 1 week and iPTH levels should be monitored within 1 to 4 weeks. Once target levels are achieved, decrease monitoring to every 3 months.

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