**2.1 Dietary phosphorus restriction**

Dietary phosphorus assessment and restriction is the cornerstone of the treatment of hyperphosphatemia. Educational support and dietary guidelines should be offered to the patients by a skilled dietician. Restriction of dietary phosphorus intake, however, requires a reduction in oral protein intake, as protein-rich foods are the main source of dietary phosphorus (Shinaberger et al., 2008). Lowering protein intake can lead to malnutrition and protein-energy wasting and thereby increasing mortality in dialysis patients (Lacson et al., 2007). It is very important to avoid concomitant malnutrition by forced dietary protein restriction, as protein restriction as means to lower dietary phosphorus intake may outweigh the benefit of controlled phosphorus and may lead to greater mortality (Shinaberger et al., 2008). One possibility for overcoming the problem of concordant overall protein restriction and the risk of malnutrition with reduced dietary phosphorus intake would be to avoid phosphorus-rich ingredients that are added to processed foods and beverages (Sherman & Mehta, 2009a, 2009b). Contrary to natural sources of organic phosphorus, such as meat or dairy products, such phosphorus sources are dissociated from protein intake. Reducing the consumption of such phosphorus additives might help to decrease phosphorus intake without the risk of protein-energy wasting (Sullivan et al., 2009). Additionally, the intake of protein sources with low phosphorus to protein ratios might further help to limit phosphorus intake (Noori et al., 2010). Nutritional guidelines recommend a maximum of 800 to 1000 mg (25 to 35 mmol) daily dietary phosphorus intake (Fouque et al., 2007). Nevertheless, dietary modifications alone are generally not sufficient to reduce phosphorus intake sufficiently in most patients, but help to save phosphate binders and probably reduce the high pill burden.

### **2.2 Phosphate binders**

The use of oral phosphate binders to block intestinal phosphorus absorption has been shown to effectively reduce serum phosphorus levels irrespective of the phosphate binder

renal phosphorus reabsorption and increase renal phosphorus excretion. FGF23 also suppresses calcitriol (1,25(OH)2D3) production, which diminishes intestinal phosphorus absorption but allows increases in PTH levels. Whereas FGF23 suppresses PTH secretion in normal parathyroid glands, resistance to its effect occurs with further loss of kidney function because of decreased Klotho and FGF receptor 1 expression in the parathyroid glands and the kidney. Thus, as chronic kidney disease progresses to late stages, these homeostatic mechanisms are inevitably overwhelmed, hyperphosphatemia ensues, and the

Robust observational data show a clear association of higher serum phosphorus levels with cardiovascular events and mortality (Block et al., 1998, 2004). The exact threshold above which risk significantly increases is not definitely known and varies across the studies from 5.0 to 7.0 mg/dL (1.6 to 2.3 mmol/L) (Covic et al., 2009). However, it has never been determined in randomized placebo-controlled trials whether treating hyperphosphatemia to specific target ranges improves clinical patient outcomes. The KDIGO guidelines therefore suggest to decrease serum phosphorus levels toward the reference range in patients with

Therapeutic interventions to treat hyperphosphatemia include restriction of dietary phosphorus intake, administration of phosphate binders and increasing the frequency or

Dietary phosphorus assessment and restriction is the cornerstone of the treatment of hyperphosphatemia. Educational support and dietary guidelines should be offered to the patients by a skilled dietician. Restriction of dietary phosphorus intake, however, requires a reduction in oral protein intake, as protein-rich foods are the main source of dietary phosphorus (Shinaberger et al., 2008). Lowering protein intake can lead to malnutrition and protein-energy wasting and thereby increasing mortality in dialysis patients (Lacson et al., 2007). It is very important to avoid concomitant malnutrition by forced dietary protein restriction, as protein restriction as means to lower dietary phosphorus intake may outweigh the benefit of controlled phosphorus and may lead to greater mortality (Shinaberger et al., 2008). One possibility for overcoming the problem of concordant overall protein restriction and the risk of malnutrition with reduced dietary phosphorus intake would be to avoid phosphorus-rich ingredients that are added to processed foods and beverages (Sherman & Mehta, 2009a, 2009b). Contrary to natural sources of organic phosphorus, such as meat or dairy products, such phosphorus sources are dissociated from protein intake. Reducing the consumption of such phosphorus additives might help to decrease phosphorus intake without the risk of protein-energy wasting (Sullivan et al., 2009). Additionally, the intake of protein sources with low phosphorus to protein ratios might further help to limit phosphorus intake (Noori et al., 2010). Nutritional guidelines recommend a maximum of 800 to 1000 mg (25 to 35 mmol) daily dietary phosphorus intake (Fouque et al., 2007). Nevertheless, dietary modifications alone are generally not sufficient to reduce phosphorus intake sufficiently in most patients, but help to save phosphate binders

The use of oral phosphate binders to block intestinal phosphorus absorption has been shown to effectively reduce serum phosphorus levels irrespective of the phosphate binder

levels of PTH and FGF23 increase progressively (Cunningham et al., 2011).

chronic kidney disease 5D (KDIGO, 2009).

**2.1 Dietary phosphorus restriction** 

and probably reduce the high pill burden.

**2.2 Phosphate binders** 

length of dialysis sessions.

class. Although no placebo-controlled randomized trial has been done so far to prove that reduction in serum phosphorus by the use of phosphate binders improves patient outcomes, a recent prospective observational study in a large number of incident dialysis patients has shown that the use of any phosphate binder (versus none) offers a clear survival benefit independent of absolute serum phosphorus concentration and co-medication (Isakova et al., 2009).

Available phosphate binders include the calcium salts calcium acetate and calcium carbonate, aluminium hydroxide, the polymeric anion-exchange resins sevelamer hydrochloride and sevelamer carbonate, lanthanum carbonate and the newer so far not well studied compounds ferric citrate, SBR759 (iron-based), magnesium/calcium carbonate and magnesium carbonate/calcium acetate. They differ in composition, phosphate-binding capacity, form and have specific potential advantages and disadvantages, which are summarized in Table 1.

Considering the different agents there are no data at present to favour one phosphate binder, because there is no proven superiority of any phosphate binder or binder class for relevant clinical outcomes. According to a recent systematic review and meta-analysis of available randomized controlled trials all phosphate binders decrease serum phosphorus levels compared with placebo. The newer drugs sevelamer hydrochloride and lanthanum carbonate do not result in superior control of biochemical parameters compared with calcium salts. In contrast, in head-to-head studies calcium salts enable a greater reduction of serum phosphorus than sevelamer hydrochloride. Whereas both calcium salts (calcium acetate and carbonate) do not differ with regard to serum calcium levels, sevelamer hydrochloride and lanthanum carbonate are associated with significantly lower rates of treatment-related hypercalcemia, which may result in decreased cardiovascular calcification. However, the finding of slower or less progression of cardiovascular calcification in sevelamer-treated patients is inconsistent across the studies. Studies revealed no difference in PTH suppression when comparing calcium acetate with calcium carbonate or lanthanum



Management of Secondary Hyperparathyroidism in Hemodialysis Patients 337

carbonate with calcium carbonate, but found a significantly lower PTH reduction with sevelamer hydrochloride in comparison to calcium salts. When all studies were pooled, gastrointestinal side effects occurred more often with sevelamer hydrochloride than with calcium salts. With the use of sevelamer hydrochloride significantly lower serum bicarbonate is found, aggravating already existing metabolic acidosis. The new formula of sevelamer carbonate does not negatively influence acid-base status. A possible advantage of sevelamer is its significant reduction of LDL-cholesterol. However, no difference in all-cause mortality could be found comparing calcium acetate and carbonate, or sevelamer with calcium salts. All-cause mortality as endpoint has not been studied with all other phosphate

Hypercalcemia is a known side effect of calcium salts, especially when combined with vitamin D receptor activators. Persistent hypercalcemia necessitates a dose reduction or cessation of calcium salts as phosphate binders. The KDOQI guidelines suggest limiting the daily calcium intake from calcium-containing phosphate binders to 1500 mg per day for elemental calcium and 2000 mg per day for total intake of elemental calcium including the dietary calcium content (KDOQI, 2003). Nevertheless, there is no data available to recommend a specific upper limit of a safe amount of calcium intake. Restrictive use of calcium-based phosphate binders may be considered in the following situations (Cozzolino

Although very effective, a prolonged (>3 months continuously, or >6 months cumulative) use of aluminium hydroxide should be avoided because of the potential toxicity of accumulated aluminium leading to encephalopathy, osteomalacia and anemia (Goldsmith et

Irrespective of the phosphate binder class the successful practical management of

A new and promising concept for the management of hyperphosphatemia was recently developed to enable patients to self-adjust the phosphate binder dose in relation to the phosphorus content of each individual meal: "Phosphate Education Program" (PEP) (Ahlenstiel et al., 2010). Patients are taught to eye-estimate the meal phosphorus content based on "phosphate units" (PU; 1 PU is defined per 100 mg of phosphorus per serving size of the meal) and then phosphate binders are prescribed dependent on an individual phosphate binder/PU ratio. This concept is similar to the individualized adjustments of

Novel agents under development for the treatment of hyperphosphatemia are MCI-196 (colestilan) (Locatelli et al., 2010), a non-metallic anion-exchange resin, and niacin and nicotinamid, which probably directly inhibit the sodium-dependent phosphate

concomitant dietary phosphorus restriction (especially phosphorus-rich additives)

individual dosing with respect to eating habits and serum phosphorus level

insulin dose to carbohydrate intake in the treatment of diabetes mellitus.

cotransporter Na-Pi-2b in the gastrointestinal tract (Muller et al., 2007).

binders (Navaneethan et al., 2009).

et al., 2011; Goldsmith et al., 2010): presence of cardiovascular disease

evidence of adynamic bone disease

 older age (>65 years) diabetes mellitus

hypercalcemia

al., 2010).

presence of vascular or valvular calcification

hyperphosphatemia with phosphate binders includes:

administration of phosphate binders with the meal

Table 1. Overview of available phosphate binders (adapted from KDOQI, 2003; KDIGO, 2009; Tonelli et al., 2010; Uhlig et al., 2010). Abbrevations: Ca2+, calcium; HCl, hydrochloride; Mg, magnesium; CO3, carbonate; NA, not available.

carbonate with calcium carbonate, but found a significantly lower PTH reduction with sevelamer hydrochloride in comparison to calcium salts. When all studies were pooled, gastrointestinal side effects occurred more often with sevelamer hydrochloride than with calcium salts. With the use of sevelamer hydrochloride significantly lower serum bicarbonate is found, aggravating already existing metabolic acidosis. The new formula of sevelamer carbonate does not negatively influence acid-base status. A possible advantage of sevelamer is its significant reduction of LDL-cholesterol. However, no difference in all-cause mortality could be found comparing calcium acetate and carbonate, or sevelamer with calcium salts. All-cause mortality as endpoint has not been studied with all other phosphate binders (Navaneethan et al., 2009).

Hypercalcemia is a known side effect of calcium salts, especially when combined with vitamin D receptor activators. Persistent hypercalcemia necessitates a dose reduction or cessation of calcium salts as phosphate binders. The KDOQI guidelines suggest limiting the daily calcium intake from calcium-containing phosphate binders to 1500 mg per day for elemental calcium and 2000 mg per day for total intake of elemental calcium including the dietary calcium content (KDOQI, 2003). Nevertheless, there is no data available to recommend a specific upper limit of a safe amount of calcium intake. Restrictive use of calcium-based phosphate binders may be considered in the following situations (Cozzolino et al., 2011; Goldsmith et al., 2010):


336 Progress in Hemodialysis – From Emergent Biotechnology to Clinical Practice

600 to 1800 mg (pill burden dependent on content per tablet)

2400 to 9600 mg (3 to 12 tablets)

2400 to 9600 mg (3 to 12 tablets, 1 to 4 packets)

very effective phosphatebinding capacity

effective phosphatebinding capacity, no Ca2+ and metal content, reduces

LDLcholesterol, possible potential for reduced calcification

same as sevelamer-HCl, but lower risk of metabolic acidosis

effective phosphatebinding capacity, no Ca2+, chewable, reduced pill burden

effective, potential for lower Ca2+ load than pure Ca2+ based binders

potential for aluminium toxicity, gastrointestinal side

costs, potential for decrease in

bicarbonate levels, in presence of hypocalcemia need for Ca2+ supplement, higher risk of gastrointestinal side effects compared to

effects

Ca2+ salts

assumed to have same disadvantages as sevelamer-HCl except decrease in bicarbonate levels, less well studied

costs, gastrointestinal side effects, potential for accumulation

potential for hypermagnesemia, gastrointestinal side effect, not well studied

potential for iron accumulation, not well studied, gastrointestinal side effects, less effective than Ca2+ salts

accumulation, not well studied (1 phase I trial), gastrointestinal side effects, hypocalcemia

powder form potential for iron

22.3 mg phosphate per 5 ml, 18.8 mg phosphate per 1000 mg

phosphate per 800 mg sevelamer-HCl

sevelamer-HCl

NA 750 to 3750 mg (3 to 5 chewable tablets)

NA 705/1305 mg

Table 1. Overview of available phosphate binders (adapted from KDOQI, 2003; KDIGO, 2009; Tonelli et al., 2010; Uhlig et al., 2010). Abbrevations: Ca2+, calcium; HCl, hydrochloride;

to 2820/5220 mg (3 to 12 tablets)

**Aluminium hydroxide** 

**Sevelamer-HCl** 

**Sevelamer carbonate** 

**Lanthanum carbonate** 

**Magnesium carbonate/cal cium acetate** 

**SBR759**  (polymeric complex of starch with ferric iron)

tablet, capsule, liquid

tablet, powder

chewable tablet

**Ferric citrate** capsule 176 mg

Varying with 100 to 600 mg aluminium per tablet

tablet none 64 mg

none same as

250, 500, 750 or 1000 mg elemental lanthanum per tablet

tablet 60 mg Mg per 235 mg MgCO3, 110 mg elemental Ca2+ per 435 mg Ca2+ acetate

> elemental iron per 1g ferric citrate

powder 1.25 g per sachet

Mg, magnesium; CO3, carbonate; NA, not available.

Although very effective, a prolonged (>3 months continuously, or >6 months cumulative) use of aluminium hydroxide should be avoided because of the potential toxicity of accumulated aluminium leading to encephalopathy, osteomalacia and anemia (Goldsmith et al., 2010).

Irrespective of the phosphate binder class the successful practical management of hyperphosphatemia with phosphate binders includes:


A new and promising concept for the management of hyperphosphatemia was recently developed to enable patients to self-adjust the phosphate binder dose in relation to the phosphorus content of each individual meal: "Phosphate Education Program" (PEP) (Ahlenstiel et al., 2010). Patients are taught to eye-estimate the meal phosphorus content based on "phosphate units" (PU; 1 PU is defined per 100 mg of phosphorus per serving size of the meal) and then phosphate binders are prescribed dependent on an individual phosphate binder/PU ratio. This concept is similar to the individualized adjustments of insulin dose to carbohydrate intake in the treatment of diabetes mellitus.

Novel agents under development for the treatment of hyperphosphatemia are MCI-196 (colestilan) (Locatelli et al., 2010), a non-metallic anion-exchange resin, and niacin and nicotinamid, which probably directly inhibit the sodium-dependent phosphate cotransporter Na-Pi-2b in the gastrointestinal tract (Muller et al., 2007).

Management of Secondary Hyperparathyroidism in Hemodialysis Patients 339

Treatment of sHPT with active vitamin D receptor activators (VDRA) is a well established therapeutic modality, and current practice guidelines recommend to treat patients with elevated and/or increasing PTH levels with a VDRA (KDIGO, 2009). Observational studies are indicating a survival benefit of VDRA in hemodialysis patients in comparison with patients without VDRA treatment (Teng et al., 2003, 2005; Tentori et al., 2006; Naves-Diaz et al., 2008). Again, prospective controlled randomised clinical trials indicating a benefit on patient-level clinical outcomes with VDRA therapy are missing but strongly awaited. Calcitriol, the physiological VDRA, is the natural regulator of parathyroid gland function and growth and exerts its effect on PTH secretion by inhibiting mRNA synthesis through its action on the vitamin D receptor (VDR), a highly specific receptor that acts as a transcription factor. In addition, calcitriol is able to inhibit PTH secretion by increasing calcium absorption in the intestine, while also increasing bone resorption and, consequently, calcium release from bone. Moreover, calcitriol regulates the expression of its own receptor, stimulating its synthesis. The deficit of calcitriol observed in hemodialysis patients as well as a transformation into nodular hyperplasia with progressive sHPT is associated with a decrease in VDR levels in the parathyroid gland. Decreased VDR expression may than cause resistance to VDRA. VDRA generally control sHPT well in patients with moderately increased hypertrophic glands and less well in patients with enlarged hyperplastic glands and should therefore be started early in the development of sHPT (Cunningham et al., 2011). Beyond the classical endocrine effects on parathyroid gland, bone and intestine, the pleiotropic paracrine and autocrine effects of vitamin D have been associated with improvement of cardiovascular risk factors, including increased renin activity, hypertension, inflammation, insulin resistance, diabetes, albuminuria

Besides the native active hormone calcitriol (1,25(OH)2D3), the two prodrugs alfacalcidol (1(OH)D3) and doxercalciferol (1(OH)D2) and the two vitamin D analogues paricalcitol (19 nor-1,25(OH)2D2) and maxacalcitol (22-oxa-1,25(OH)2D3) can be used. Paricalcitol and maxacalcitol (oxacalcitriol) bind directly to the VDR, whereas doxercalciferol and alfacalcidol need an enzymatic 25-hydroxylation activation step in the liver. So far no prospective, placebo-controlled and blinded clinical trial involving 22-oxacalcitriol, paricalcitol, or doxercalciferol has yet demonstrated additional clinical benefits when compared with calcitriol, nor have any studies been published showing that either calcitriol or alfacalcidol has an advantage over the other with respect to biochemical or clinical end points (Cunningham & Zehnder, 2011). Therefore, low dose therapy with calcitriol (e.g. 0.25 µg/d orally or 0.25 µg thrice weekly orally or intravenously as a starting dose) is recommended with elevated or increasing PTH levels (KDIGO, 2009). Characteristics and

oral calcitriol equivalent doses of various available VDRA are presented in Table 3.

According to current practice guidelines, the target range for PTH is now 2-9 times the upper limit of the normal range (KDIGO, 2009; Uhlig et al., 2010; Goldsmith et al., 2010). This wide range takes into account a significant interassay variability of values obtained with different commercial PTH assays (Koller et al., 2004; Souberbielle et al., 2010), inability to uniformly predict bone histologic and histomorphometric states by means of PTH within this range and the epidemiological observation of increased all-cause mortality starting from PTH values >400 to 600 pg/mL (Uhlig et al., 2010). If there is no successful response with PTH reduction into the suggested target range, or dose-limiting side effects occur, especially hypercalcemia and hyperphosphatemia, a calcimimetic can be initiated instead or combined

**3.2 Vitamin D receptor activators** 

and an improved immune response.

with a low dose of VDRA.
