**4. Management of hyperphosphatemia in hemodialysis patients**

### **4.1 Target of management**

As elevated serum phosphorus and calcium levels are associated with vascular calcification and cardiovascular mortality in CKD, priority should be given to normalization of these parameters. It is generally accepted that adequate control of serum phosphorus remains a cornerstone in the clinical management of patients with CKD not only to attenuate the progression of secondary hyperparathyroidism but also possibly to reduce the risk for vascular calcification and cardiovascular mortality. A Ca x P more tan 72 mg2/dl2 is associated with a significant increase in the relative risk (RR) of mortality (RR = 1.34) compared with Ca x P less than 50 mg2/dl2 (Cozzolino et al., 2001). In a study in patients on hemodialysis, those who did not experience valvular calcification had maintained Ca x P at an average of 51 mg2/dl2 in the 6 months prior to the study, while those who did experience valvular calcification had an average Ca x P of 60 mg2/dl2 (Ribeiro et al., 1998). The target of treatment should be to maintain serum phosphorus level less than 5 mg/dl with serum calcium level less than 10 mg/dl to prevent cardio vascular consequences. This will allow the maintenance of Ca x P less than 50 mg2/dl2, a level which available evidence has so far shown not to promote calcification or increase mortality (Ribeiro et al., 1998).

High FGF23 levels are more strongly associated with kidney disease progression, left ventricular hypertrophy, vascular disease, and mortality than serum phosphorus levels, and were most predictive of adverse events in patients with normal serum phosphorus (Thadhani et al., 2008; Oliveira et al., 2010). Dietary phosphate binders can lower FGF23 in CKD (Oliveira et al., 2010). Management of hyperphosphatemia relies on dietary restriction, the use of phosphate binders and dialysis.

### **4.2 Dietary restriction of phosphate intake**

The average diet in North America and Europe contains approximately 1,000 to 1,500 mg of phosphorus per day (Willett & Buzzard, 1998). Dietary approach to phosphate retention in advanced renal failure patients, dietary approach to phosphate reduction is an important step in the treatment of hyperphosphatemia. The level of expression of klotho mRNA was greatly reduced in the kidneys of all chronic renal failure patients. Dietary phosphate restriction induced klotho expression, which enhances the beneficial effect of phosphate restriction in patients with chronic renal failure and or on hemodialysis. However, dietary restriction cannot considerably reduce the level of phosphate retention. As dialysis patients tend to need higher levels of protein due to the losses via dialysis, tight restriction on phosphate is difficult without compromising a patient's nutritional status. Because most dietary phosphate is contained in protein-rich foods, there is some concern about excessive protein restriction. In fact, the minimum amount of protein of 1.2 g/kg body weight/day, recommended to prevent malnutrition makes planning a diet with less than 1 g of phosphorus impossible (Kopple, 2001; Eknoyan et al., 2003). Recommendations that call for 1.0 to 1.2 g/kg/day protein will usually obligate a phosphorus intake of 800 to 1,400 mg/day. Net phosphorus absorption averages 60% to 70% of intake (Delmez & Slatopolsky, 1992; Sheikh et al., 1989), however, this percentage can rise as high as 86% of ingested phosphate with calcitriol use and decrease to 30% to 40% of ingested phosphate with optimal binder usage.(Sheikh et al., 1989; Delmez & Slatopolsky, 1992).

Other foods that are high in phosphate are processed foods such as processed meats which have phosphate based additives to improve the consistency and appearance of the food. Since 1990, intake of phosphate from additives has doubled and has been 1,000 mg in USA (Calvo & Park, 1996). This is the amount that some renal patients are advised for the whole day from all food groups (James & Jackson, 2002). As people are becoming more reliant on processed and packaged meals due to convenience, phosphate from these sources needs to be considered when advising on diet. Fresh meat is considered suitable for someone following a phosphate restriction, however processed foods may in fact be providing much more phosphate than realised (Sullivan et al., 2007). Beverages such as sodas, juices and sport drinks also contain phosphate additives (Murphy-Gutekunst, 2007). It has been estimated that for a person on hemodialysis the average phosphate removal per day is 300 mg (Vaithilingham et al., 2004). This leaves the patient with a positive balance for phosphate.

### **4.3 Hemodialysis**

320 Progress in Hemodialysis – From Emergent Biotechnology to Clinical Practice

and decreased perfusion of coronary arteries during diastole (Blacher et al., 1998; London, 2003; Speer & Giachelli, 2004). Recent studies also demonstrated that elevated FGF23 levels were associated with arterial stiffness, increased left ventricular mass index and increased prevalence of left ventricular hypertrophy in patients with CKD (Hsu & Wu, 2009; Mirza et

As elevated serum phosphorus and calcium levels are associated with vascular calcification and cardiovascular mortality in CKD, priority should be given to normalization of these parameters. It is generally accepted that adequate control of serum phosphorus remains a cornerstone in the clinical management of patients with CKD not only to attenuate the progression of secondary hyperparathyroidism but also possibly to reduce the risk for vascular calcification and cardiovascular mortality. A Ca x P more tan 72 mg2/dl2 is associated with a significant increase in the relative risk (RR) of mortality (RR = 1.34) compared with Ca x P less than 50 mg2/dl2 (Cozzolino et al., 2001). In a study in patients on hemodialysis, those who did not experience valvular calcification had maintained Ca x P at an average of 51 mg2/dl2 in the 6 months prior to the study, while those who did experience valvular calcification had an average Ca x P of 60 mg2/dl2 (Ribeiro et al., 1998). The target of treatment should be to maintain serum phosphorus level less than 5 mg/dl with serum calcium level less than 10 mg/dl to prevent cardio vascular consequences. This will allow the maintenance of Ca x P less than 50 mg2/dl2, a level which available evidence has so far

**4. Management of hyperphosphatemia in hemodialysis patients** 

shown not to promote calcification or increase mortality (Ribeiro et al., 1998).

High FGF23 levels are more strongly associated with kidney disease progression, left ventricular hypertrophy, vascular disease, and mortality than serum phosphorus levels, and were most predictive of adverse events in patients with normal serum phosphorus (Thadhani et al., 2008; Oliveira et al., 2010). Dietary phosphate binders can lower FGF23 in CKD (Oliveira et al., 2010). Management of hyperphosphatemia relies on dietary restriction,

The average diet in North America and Europe contains approximately 1,000 to 1,500 mg of phosphorus per day (Willett & Buzzard, 1998). Dietary approach to phosphate retention in advanced renal failure patients, dietary approach to phosphate reduction is an important step in the treatment of hyperphosphatemia. The level of expression of klotho mRNA was greatly reduced in the kidneys of all chronic renal failure patients. Dietary phosphate restriction induced klotho expression, which enhances the beneficial effect of phosphate restriction in patients with chronic renal failure and or on hemodialysis. However, dietary restriction cannot considerably reduce the level of phosphate retention. As dialysis patients tend to need higher levels of protein due to the losses via dialysis, tight restriction on phosphate is difficult without compromising a patient's nutritional status. Because most dietary phosphate is contained in protein-rich foods, there is some concern about excessive protein restriction. In fact, the minimum amount of protein of 1.2 g/kg body weight/day, recommended to prevent malnutrition makes planning a diet with less than 1 g of phosphorus impossible (Kopple, 2001; Eknoyan et al., 2003). Recommendations that call for 1.0 to 1.2 g/kg/day protein will usually obligate a phosphorus intake of 800 to 1,400

al., 2009; Gutierrez et al., 2009).

**4.1 Target of management** 

the use of phosphate binders and dialysis.

**4.2 Dietary restriction of phosphate intake** 

The clearance of phosphate varies among the different modalities of dialysis. Ideally, adequate dialysis in any form would remove adequate amounts of all uremic toxins, including phosphate. Unfortunately, conventional thrice-weekly hemodialysis (4 h duration) removes approximately 900 mg of phosphorus each treatment (an average of only 300 mg/day) (Gotch et al., 2003). Increasing the dosage of dialysis, preferably to lengthy three times per week dialysis, hemodiafiltration, or, even better, daily/nightly dialysis may prevent phosphorus retention and even require no dietary phosphate restriction or the withdrawal of phosphate binders (Maduell et al., 2003; Benaroia et al., 2008). However, regular dialysis treatment is not able to remove all the phosphorus ingested with a diet containing protein of 1.0 - 1.2 g/kg/day (Mallick & Gokal, 1999).

### **4.4 Phosphate binders**

Isakova et al analyzed a prospective cohort study of 10,044 incident hemodialysis patients at Fresenius Medical Care facilities in 2004 and 2005 comparing 1-year all-cause mortality among patients who were treated with phosphate binders (Isakova et al., 2009). In an intention-to-treat analysis, they compared patients who began treatment with any phosphate binder during the first 90 days after initiating hemodialysis, with those who remained untreated during that period. Treatment with phosphate binders was independently associated with decreased mortality compared with no treatment. In the unmatched cohort, the phosphate binder-treated group had a relative risk reduction of 42%, while in the intention-to-treat and as-treated analyses, the magnitude of the survival benefit ranged between 18% and 30% in multivariate models. The association between use of phosphorus binders and survival was observed within each quartile of baseline serum phosphorus except the lowest. Results from human data suggest that lowering of phosphorus levels by intake of phosphate binders will substantially reduce serum FGF-23 levels (Koiwa et al., 2005; Pande et al., 2006). In this prospective observational study, treatment with phosphate binders was associated with a reduced 1-year mortality among incident hemodialysis patients (Isakova et al., 2009).

Complications and Managements of Hyperphosphatemia in Dialysis 323

Absorption (2,000-4,000 mg/week)

**(900 mg/week)**

Successful control of phosphate is one of the key aspects in the management of dialysis patients (Rodriguez-Benot et al., 2005; Young et al., 2004, Young et al., 2005), However, numerous studies have revealed the difficulty in achieving phosphorus targets less than 5.5 mg/dl (Arenas et al., 2006; Lorenzo et al., 2006: Wei et al., 2006), despite the wide variety of drugs available for its treatment (Joy & Finn, 2003; Sprague, 2007; Arenas et al., 2008). Both endothelial dysfunction and medial calcification are closely associated with development of cardiovascular disease. It is well known that long-term exposure to phosphate, generally observed in end-stage renal failure patients, can mediate vascular calcification (Jono et al., 2000; Giachelli, 2003). Dietary high phosphate loading can be involved in the postprandial elevation of serum phosphorus level, and this short-term exposure to phosphate was

The goals of therapy have been to reduce phosphorus intake with low protein diet and phosphate binders. Since low protein diet is thought to be induce malnutrition, it is thought that strict adherence to a low protein diet is not practical. A diet rich in proteins is usually also rich in phosphorus. However, proteins with very different phosphorus contents can provide equivalent nutritional value, as can be seen from the difference in phosphorus content between meat, cheese, and eggs. Egg white is an excellent example of food with a high level of protein but low phosphorus content. Moe et al. demonstrates the importance of

Phosphate pool (blood)

Bone and soft tissue

**Hemodialysis (900 mg/week)**

Dietary intake Protein non-restricted **restricted** (mg/kg/day) 1.0-1.2 **0.3-0.35**

(mg/week) 5,600-10,000 **2,250** (mg/day) 800-1,400 **320**

> Stool (3,000-6,000 mg/week) **(1,350 mg/week)**

Fig. 3. Phosphate balance in hemodialysis patient

enough to decrease endothelium-dependent vasodilation.

**5. Conclusion** 

Those in restricted protein and phosphate intake are shown in bold.

Intestine

Phosphorus

Phosphate -binder

Sevelamer hydrochloride and lanthanum carbonate are a phosphate binders containing neither calcium nor aluminium, and are useful in those being administered concurrent vitamin D to reduce the potential for hypercalcemia. Attenuation in the progression of coronary artery calcification, after 6 and 12 months, was shown in hemodialysis patients treated with sevelamer, with reduced serum calcium, compared with patients on calcium carbonate (Chertow et al., 2002). A more recent randomized study of 114 incident hemodialysis patients demonstrated a survival advantage for patients on sevelamer compared with calcium carbonate after 18-month follow up (Block et al., 2007). A further beneficial effect of sevelamer has been proved on markers of coronary artery and aortic calcification compared with calcium based phosphate binders (Chertow et al., 2002). The attenuation of vascular and, in particular, coronary calcifications compared with calciumbased phosphate binders in end-stage kidney disease patients under dialysis has been studied by electron beam computed tomography (Raggi, 2002; Raggi, 2004). High doses of sevelamer (3.2–8 g/day) are necessary to bring hyperphosphatemia back to target level, and the number of pills per day (about 8 x 800 mg tablets) may certainly be a conditioning factor for the patient's compliance (Chertow et al., 2002).

Patients with end-stage kidney disease treated with lanthanum carbonate up to 2.5–3.8 g/day for up to 2 years have been reported to obtain effective reduction of serum phosphorus level (Finn, 2006). Lanthanum-carbonate-treated patients have, also been shown to reach a significantly reduced calcium/phosphate product and parathyroid hormone level compared with the placebo (Joy & Finn, 2009). Lanthanum carbonate, therefore, is an effective, at least as effective as calcium carbonate, well-tolerated phosphate binder (Hutchison, 2004; Hutchison et al., 2006). However, despite the very encouraging results, further studies involving larger numbers of patients are needed to definitively establish the long-term safety of lanthanum regarding tissue deposition, as well as its efficacy on vascular calcifications or outcomes in treated patients, which also need to be confirmed in the long term.

#### **4.5 Combination in treatment**

A multiple-factor approach can be used to reduce serum phosphate including reduced phosphorus intake in the diet, using phosphate binders efficiently and avoidance of under- dialysis. The patient's diet should be high in nutrition but with the lowest possible phosphorus content. Since dietary control of phosphorus intake and dialysis removal are usually not sufficient, phosphate binders are usually needed as adjuvants to increase fecal excretion (Bover et al; 2005). For an optimal protein diet of 1-1.2 g/kg/day, the phosphorus intake was 778-1,444 mg/day and 5,500-10,000 mg/week. Dialysis has limited ability for phosphate control, although phosphate removal by hemodialysis is very much a time-dependent process. The amount of phosphorus removed by hemodialysis, extrapolated to an average week, is 250-300 mg/day. The introduction of non-calciumbased phosphate binders has enabled a reduction in the total phosphate load and provides a useful tool in the prevention of vascular calcification in CKD. The use of phosphate binders may decrease the phosphorus absorbed from the diet to 40% (Llach & Bover, 2000). In these circumstances, 320 mg of phosphorus and 21g of protein (0.3-0.35g of protein/kg/day) intake should be the critical value above which a positive balance of phosphate may occur (Fig. 3).

Sevelamer hydrochloride and lanthanum carbonate are a phosphate binders containing neither calcium nor aluminium, and are useful in those being administered concurrent vitamin D to reduce the potential for hypercalcemia. Attenuation in the progression of coronary artery calcification, after 6 and 12 months, was shown in hemodialysis patients treated with sevelamer, with reduced serum calcium, compared with patients on calcium carbonate (Chertow et al., 2002). A more recent randomized study of 114 incident hemodialysis patients demonstrated a survival advantage for patients on sevelamer compared with calcium carbonate after 18-month follow up (Block et al., 2007). A further beneficial effect of sevelamer has been proved on markers of coronary artery and aortic calcification compared with calcium based phosphate binders (Chertow et al., 2002). The attenuation of vascular and, in particular, coronary calcifications compared with calciumbased phosphate binders in end-stage kidney disease patients under dialysis has been studied by electron beam computed tomography (Raggi, 2002; Raggi, 2004). High doses of sevelamer (3.2–8 g/day) are necessary to bring hyperphosphatemia back to target level, and the number of pills per day (about 8 x 800 mg tablets) may certainly be a conditioning factor

Patients with end-stage kidney disease treated with lanthanum carbonate up to 2.5–3.8 g/day for up to 2 years have been reported to obtain effective reduction of serum phosphorus level (Finn, 2006). Lanthanum-carbonate-treated patients have, also been shown to reach a significantly reduced calcium/phosphate product and parathyroid hormone level compared with the placebo (Joy & Finn, 2009). Lanthanum carbonate, therefore, is an effective, at least as effective as calcium carbonate, well-tolerated phosphate binder (Hutchison, 2004; Hutchison et al., 2006). However, despite the very encouraging results, further studies involving larger numbers of patients are needed to definitively establish the long-term safety of lanthanum regarding tissue deposition, as well as its efficacy on vascular calcifications or outcomes in treated patients, which also need to be confirmed in the long

A multiple-factor approach can be used to reduce serum phosphate including reduced phosphorus intake in the diet, using phosphate binders efficiently and avoidance of under- dialysis. The patient's diet should be high in nutrition but with the lowest possible phosphorus content. Since dietary control of phosphorus intake and dialysis removal are usually not sufficient, phosphate binders are usually needed as adjuvants to increase fecal excretion (Bover et al; 2005). For an optimal protein diet of 1-1.2 g/kg/day, the phosphorus intake was 778-1,444 mg/day and 5,500-10,000 mg/week. Dialysis has limited ability for phosphate control, although phosphate removal by hemodialysis is very much a time-dependent process. The amount of phosphorus removed by hemodialysis, extrapolated to an average week, is 250-300 mg/day. The introduction of non-calciumbased phosphate binders has enabled a reduction in the total phosphate load and provides a useful tool in the prevention of vascular calcification in CKD. The use of phosphate binders may decrease the phosphorus absorbed from the diet to 40% (Llach & Bover, 2000). In these circumstances, 320 mg of phosphorus and 21g of protein (0.3-0.35g of protein/kg/day) intake should be the critical value above which a positive balance of

for the patient's compliance (Chertow et al., 2002).

term.

**4.5 Combination in treatment** 

phosphate may occur (Fig. 3).

Fig. 3. Phosphate balance in hemodialysis patient Those in restricted protein and phosphate intake are shown in bold.

Successful control of phosphate is one of the key aspects in the management of dialysis patients (Rodriguez-Benot et al., 2005; Young et al., 2004, Young et al., 2005), However, numerous studies have revealed the difficulty in achieving phosphorus targets less than 5.5 mg/dl (Arenas et al., 2006; Lorenzo et al., 2006: Wei et al., 2006), despite the wide variety of drugs available for its treatment (Joy & Finn, 2003; Sprague, 2007; Arenas et al., 2008). Both endothelial dysfunction and medial calcification are closely associated with development of cardiovascular disease. It is well known that long-term exposure to phosphate, generally observed in end-stage renal failure patients, can mediate vascular calcification (Jono et al., 2000; Giachelli, 2003). Dietary high phosphate loading can be involved in the postprandial elevation of serum phosphorus level, and this short-term exposure to phosphate was enough to decrease endothelium-dependent vasodilation.
