Phosphorus Control

Phosphate Control in Renal Disease

a report by

F o u a d A l b a a j and A l a s t a i r J H u t c h i s o n 2
1

1. Consultant Nephrologist, Queen Elizabeth and City Hospitals, Birmingham; 2. Consultant Nephrologist and Clinical Director, Renal Unit, Manchester Royal Infirmary

Hyperphosphataemia is prevalent among chronic renal failure and dialysis patients. It is known to stimulate parathyroid hormone and suppress vitamin D3 production, thereby inducing parathyroid bone disease. Furthermore, it may independently contribute to cardiac causes of death through increased myocardial calcification and enhanced vascular calcification. Therefore, phosphate control is now recognised to be of prime importance in the management of patients with chronic kidney disease (CKD). It is important to control phosphate levels early in the course of CKD in order to avoid and treat secondary hyperparathyroidism and to minimise risks of cardiovascular and soft tissue calcifications. Because of its large sphere of hydration and complex kinetics of phosphate elimination, phosphate is not easily removed by dialysis. Although long hours or slow nocturnal dialysis may be much more effective in controlling serum phosphate levels, these techniques carry with them significant logistical difficulties and are not generally applicable to all patients. Long-term dietetic restrictions are often difficult to follow and therefore oral phosphate-binding agents are required in the majority of patients. Treatment of Hyperphosphataemia Dietary Intervention Major sources of dietary phosphate include milk and cheese, eggs, meat (particularly liver, kidney and veal), fish (particularly fatty fish such as salmon and shellfish), peas, beans, lentils, soya products, bran and all bran-containing cereals, as well as other coarse-grain foods such as oatcakes. Processed foods usually contain significantly more phosphate than do natural products. The mean intake of phosphate in the UK diet is 1,260mg/day from food and 4.4mg/day from drinking water.1 The net

absorption from a mixed diet has been reported to be in the range of 5570% in adults. However, the intestinal absorption of phosphate is greatest in the jejunum and decreases along the length of the small intestine. Decreasing dietary phosphate is difficult to achieve without significant reduction in protein intake, which may put patients with renal failure at risk of malnutrition.2 Dialytic Phosphate Removal On average, only 5001,000mg of phosphate are eliminated by one dialysis treatment. The best results are obtained with the use of largesurface-area dialysers with prolonged dialysis times and high blood-flow rates. In peritoneal dialysis, the weekly removal of phosphate has been estimated at around 2,200mg, but this depends on the distribution of

phosphate control is now recognised to be of prime importance in the management of patients with chronic kidney disease.

isotonic and hypertonic peritoneal dialysis fluids.3 Haemofiltration or haemodialfiltration seem to be somewhat more effective than conventional haemodialysis, probably because of the continuous nature of these treatments.4 Kinetic studies of haemodialysis have shown that serum phosphate levels drop rapidly in the first 12 hours of treatment and then reach a plateau. The amount of phosphate removed decreases significantly in the second half of dialysis. Serum phosphate levels then rise relatively quickly in the first few hours after termination of dialysis

Fouad Albaaj is a Consultant Nephrologist at Queen Elizabeth and City Hospitals in Birmingham. His clinical and research interests lie in the area of divalent ion metabolism in chronic renal failure and renal osteodystrophy. E: falbaajfab@hotmail.com

the so-called rebound phenomenon.5 However, lengthening dialysis or using larger dialysers with higher efficacy enhances phosphate removal; this was demonstrated by the Tassin Centre (Paris, France) experience6 and by Kooisera and colleagues in The Netherlands.7 The results were most marked in the nocturnal haemodialysis schedule: serum phosphate levels were considerably lower with nocturnal haemodialysis, and patients increased their dietary phosphate intake by 50% and did not require

Alastair J Hutchison is a Consultant Nephrologist and Clinical Director of the Renal Unit at Manchester Royal Infirmary. He has clinical and research interests in renal bone disease and osteoporosis in patients who are on dialysis or have received a renal transplant, and has published approximately 70 scientific papers and book chapters in these fields. Dr Hutchison is a reviewer and referee for a variety of international journals, including Nephrology, Dialysis and Transplantation and Kidney International.

phosphate binders after the fourth month. Reduced-calcium Dialysate Reduction of the calcium concentration in dialysis fluids has been shown to reduce hyperphosphataemia without deleterious effects on bone histology in haemodialysis patients.8 Three independent studies demonstrated these effects in continuous ambulatory peritoneal dialysis (CAPD) patients using fluids with a calcium concentration of 1.25mmol/l

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Phosphate Control in Renal Disease

(instead of 1.75mmol/l).911 Moreover, it has the advantage of allowing the ingestion of larger doses of vitamin D, leading to better control of renal bone disease. On the other hand, extended treatment with lowcalcium dialysate may be associated with an increased risk of severe hyperparathyroidism unless serum calcium is carefully controlled.12

Figure 1: Efficacy of Various Phosphate-binders at Clinically Relevant pH In Vitro

100

80

Oral Phosphate-binding Agents The search for an ideal phosphate-binder has been an important goal in the management of renal bone disease since the discovery that kidney disease impairs mineral metabolism. Traditionally, aluminium- or calcium-based phosphate-binding agents have been used to treat hyperphosphataemia in chronic renal failure and dialysis patients. Although these agents effectively lower serum phosphate levels, they are associated with serious side effects. Fortunately, several new agents are now available, including sevelamer hydrochloride and lanthanum carbonate.

% phosphate binding

60

CaCo3 La2Co3

40

AI(OH)3

20

0 pH3 pH5 pH pH7

Many studies have demonstrated that both calcium carbonate and calcium acetate are effective in treating hyperphosphataemia in dialysis patients.1315 Hypercalcaemia is the most common problem (2080%) and is frequently severe enough to require withdrawal of the binder, compared with calcium carbonate in 32 stable haemodialysis patients (20 receiving calcium ketoglutarate and 12 receiving calcium carbonate). The incidence of hypercalcaemia (>2.8mmol/l) was significantly higher in the carbonate group. Furthermore, a high incidence of gastrointestinal complaints was reported in the ketoglutarate group.20 The main disadvantage of calcium ketoglutarate is its price compared with calcium acetate or carbonate. On the other hand, it has a putative anabolic effect, which may improve malnutrition in dialysis patients.21 Long-term adverse effects of calcium-containing phosphate-binders are unknown. Tumoral calcinosis and calciphylaxis are serious concerns, and these binders may increase the incidence of such problems. The Kidney Disease Outcomes Quality Initiative (K/DOQI) Clinical Practice but gastrointestinal symptoms (such as change in bowel habit, vague abdominal discomfort and dyspepsia) are often reported. Calcium carbonate does not bind phosphate optimally in all acid environments, with the binding capacity reduced in the neutral pH range (around 7) as well as in the most acidic range (around 3). Conversely, calcium acetate dissolves more easily at high gastric pH. Both acetate and carbonate are equivalent in their binding capacity, provided that calcium carbonate is taken on an empty stomach a few minutes before meals.16 Although the daily intake of calcium is halved in patients who take calcium acetate, the number of hypercalcaemic episodes is comparable. Calcium acetate is capable of binding intestinal phosphate more effectively per mmol of administered elemental calcium than is calcium carbonate. Theoretically, 1g of the elemental calcium as the carbonate would bind 43mg of phosphate, whereas 1g of calcium acetate would bind 106mg.17 Calcium alginate is a natural polyuronic acid that has been tested for its capacity as a phosphate-binder in vivo and in vitro in haemodialysis and CAPD patients.18 In 14 CAPD patients, calcium alginate did not cause significant hypercalcaemia compared with calcium carbonate. One gram of calcium alginate contains only 102mg elemental calcium, whereas calcium carbonate contains 400mg/g. However, patients achieved good phosphate control (1.6mmol/l) and did not require extra aluminium supplements (placebo or control groups were not included).19 Calcium ketoglutarate is a semi-synthetic analogue of the amino acid glutamic acid and exerts phosphate-binding properties. It was Aluminium hydroxide dissolves rapidly and binds phosphate at any pH, making it the most effective phosphate binder in vitro and in vivo. In patients taking aluminium hydroxide, plasma aluminium levels should be measured monthly. Aluminium toxicity manifestations include >2.55mmol/l or whose immunoreactive parathyroid hormone (iPTH level) is <150pg/ml (16.5pmol/l), or in patients with severe vascular and/or soft-tissue calcifications, although this latter advice is opinionbased only. Calcium citrate should be avoided in CKD, as citrate leads to increased aluminium absorption.22 Guidelines for Bone Metabolism and Disease in CKD recommended that the total dose of elemental calcium provided by calcium-based phosphate-binders should not exceed 1,500mg/day, with total calcium intake per day from diet and binders to not exceed 2,000mg. The guidelines suggest that calcium-based binders should also be avoided in dialysis patients who have a corrected plasma calcium level

The search for an ideal phosphatebinder has been an important goal in the management of renal bone disease since the discovery that kidney disease impairs mineral metabolism.

Long-term adverse effects of calcium-containing phosphatebinders are unknown.

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Phosphorus Control
potentially promising phosphate binder, although no further development has occurred.
Aluminium carbonate and hydroxide Calcium carbonate and acetate Magnesium carbonate and hydroxide Calcium ketoglutarate Calcium alginate Zirconyl chloride Nicotinamide Poly (allamine hydrochloride) (Sevelamer, Renagel) Lanthanum carbonate (Fosrenol)

Table 1: Existing Oral Phosphate-binders

Nicotinamide is not really a phosphate-binder, but an inhibitor of sodiumdependent phosphate co-transport in the small intestine. It has been found to be effective in reducing hyperphosphataemia at a mean dose of 1,000mg (i.e. two tablets) compared with calcium carbonate. It is a cheap medication that is non-reimbursable in most countries, but long-term experience is lacking.29 Sevelamer hydrochloride (Renagel) is a non-calcium-, non-metal-based

Table 2: Daily Cost of Phosphate-binders

Agent Calcium acetate (36 tablets) Titralac (640 tablets) Calcichew (36 tablets) Calcichew Forte (36 tablets) Calcium 500 (36 tablets) Calcidrink granules (1 sachet) Aluminium hydroxide (420 capsules) Sevelamer 800mg (8 capsules) Fosrenol 750mg (3 tablets) Daily cost () 0.330.66 0.10.62 0.30.61 0.661.3 0.30.61 0.91 0.241.18 5.46 5.07

phosphate-binding polymer. It is a cross-linked poly (allylamine) that forms ionic and to a lesser extent hydrogen bonds with phosphate and is completely resistant to digestive degradation and, therefore, not absorbed from the gastrointestinal tract.30 As a binder, it is at least as effective as calcium acetate, but, because of its structure, also binds certain fat-soluble vitamins such as 1,25 dihydroxyvitamin D3 and vitamin K.31 Studies demonstrate a significant decrease in phosphate levels with an associated decrease in PTH. In 172 haemodialysis patients treated for eight weeks, serum phosphate level was effectively controlled and serum total cholesterol was lowered, all without the induction of hypercalcaemia.32 Also, it was shown that its use slowed the progression of or even arrested coronary and aortic calcifications compared with the administration of calcium carbonate or acetate.33 Long-term studies confirmed that sevelamer is effective in lowering serum phosphate levels in haemodialysis patients with a corresponding reduction in calcium x phosphate product, and that the beneficial effect

osteomalacia, bone and muscle pain, iron-resistant microcytic anaemia and neurological abnormalities. Bone, brain, heart and liver are the major sites of aluminium deposition in the body, but the degree of aluminium retention does not correspond with the plasma level; therefore, the desferroxamine test is often used.23 Aluminium may be especially toxic in high-risk conditions such as postparathyroidectomy, diabetes, low turnover bone states and following reinstitution of dialysis after kidney transplantation.24 Therefore, aluminium-containing phosphate binders may be considered in some treatment-resistant cases, but only for short time periods or in patients with very short life expectancy. Low doses of magnesium hydroxide or carbonate have been used in place of, or in association with, calcium salts for the control of plasma phosphate levels. Low-dose magnesium treatment is accompanied by only slight increases in plasma magnesium concentrations and does not appear to have any long-term deleterious effects on bone mineralisation. Higher doses should not be used since they frequently lead to diarrhoea and favour the occurrence of hyperkalaemia.25 Polyuronic acid derivatives, such as sodium ferrus citrate and ferrihydride, have a significant capacity for absorbing phosphate. They are only slightly soluble in the gastrointestinal tract and thus prevent excessive uptake of iron, which makes them good candidates for phosphate-binding. In a study by Ritz et al., there was a median percentage decrease in serum phosphate of 20%, with a concomitant decrease in urinary phosphate excretion; altered bowel habit was the only reported side effect.26 The use of cross-linked iron dextran has been reported in haemodialysis patients. An added advantage may result from the small amount of iron absorbed by these often chronically irondeficient patients.27 Zirconyl chloride octahydrate has been evaluated as a dietary phosphatebinder in rats, in which it was as effective as aluminium chloride and reduced bone phosphate burden significantly.28 This compound is a

the best phosphate binder is still the one that the patient will take, so potency and pill burden are perhaps the most important considerations.

was sustained over time, but diarrhoea (16%) and pain (13%) were seen in phase III crossover studies.34 Also, one safety consideration with sevelamer is its potential to decrease plasma carbonate levels and therefore exacerbate metabolic acidosis.35 Data from two recent mortality trials, Dialysis Clinical Outcomes Revisited (DCOR) and RIND, have shown a survival benefit for patients treated with sevelamer versus those treated with CCBP.36,37 Sevelamer is more expensive than conventional binders, which has limited its prescription in some countries and increases the cost of dialysis.38 Lanthanum carbonate (Fosrenol) is a rare Earth element that has recently been launched for the treatment of hyperphosphataemia in patients with end-stage renal disease (ESRD). Lanthanum carbonate binds phosphate optimally at pH 35, while retaining good binding activity across the full range of pH 17. The relative efficacy of lanthanum carbonate was compared with aluminium hydroxide, calcium carbonate and sevelamer in a 5/6 nephrectomised rat model, with urinary phosphate measurement as a surrogate for potency of phosphate binding. It was found that lanthanum carbonate reduced urinary phosphate to the same extent as aluminium and more effectively than calcium carbonate or sevelamer.39

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Phosphorus Control
Lanthanum carbonate is highly insoluble and therefore has a low potential for accumulation compared with aluminium (0.00089% versus 0.050.1% absorption of the oral dose) and does not appear to cross the bloodbrain barrier. Also, it has no effect on the absorption of fat-soluble vitamins.40 Lanthanum carbonate has been studied in over 5,000 patients in clinical trials before launch. These studies showed good control of phosphate levels over short- and long-term follow-up (up to six years).
41,42

turnover (adynamic bone disease or osteomalacia) at baseline tended to show improved bone histology in the lanthanum carbonate group compared with those in the calcium carbonate group, where low turnover lesions persisted (71% versus 42%, respectively).43 This finding is particularly important in excluding any aluminium-like effect on osteoblast function. Thus, it appears that the evolution towards low bone turnover lesions that is often seen in calcium-treated dialysis patients is not seen with lanthanum carbonate. No correlations between bone lanthanum content, PTH levels or bone histology were found.44 Lanthanum is priced equally to sevelmer (see Table 2). Conclusion Hyperphosphataemia remains one of the major and modifiable risk factors for mortality in ESRD patients, and all means at our disposal must be used to prevent it. However, we must begin to individualise phosphate-binder therapy according to bone mineral indices and the presence of vascular calcification to make the right choice and dose, at the lowest cost. Indeed, the best phosphate binder is still the one that the patient will take, so potency and pill burden are perhaps the most important considerations from the patients perspective.

Low serum lanthanum levels were detectable in the majority of patients (0.10.8ng/l). This increase was noted for all doses administered versus baseline and levels reached a plateau early in the study, then showed no further increase. Furthermore, they were not dose-dependent and there are no reported pathological or toxic consequences associated with the increase in plasma lanthanum concentration. The incidence of adverse events was comparable to the placebo group, and it is reported that they are minimised if taken with or preferably immediately after food, and generally abate with time and continued dosing.42 The effects on bone were examined in a large-scale (98 patients) histology-based study: after one year of treatment there was a trend towards improved histology. However, the patients with low bone

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