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Alastair J Hutchison
Manchester Institute of Nephrology and Transplantation
The Royal Infirmary
Hyperphosphataemia stimulates parathyroid hormone and suppresses vitamin D3 production, inducing hyperparathyroid bone disease. It may also independently contribute to cardiac causes of death, through increased myocardial calcification and enhanced vascular calcification and cardiac microcirculatory abnormalities.
It is important to control phosphate levels early in the course of chronic kidney disease, to avoid secondary hyperparathyroidism and cardiovascular and soft tissue calcifications. Long-term dietetic restrictions are often difficult to respect, and phosphate is not easily removed by dialysis, due to a large sphere of hydration and the complex kinetics of phosphate elimination. Long slow dialysis may be effective, but requires logistics and patient acceptance. Thus, oral phosphate binders are needed to control serum levels.
Treatment of hyperphosphataemia
Hyperphosphataemia usually accompanies end-stage renal disease (ESRD) and dialysis in the absence of dietary phosphate restriction or supplemental phosphate binders. Poor phosphate control is generally associated with significant morbidity and mortality, increased hospitalisation, premature death, reduced quality of life and increased cost of care.(1–3)
Phosphate-rich diets comprise milk and cheese, eggs, meat (particularly liver, kidney and veal), fish (particularly fatty fish, such as salmon, shellfish and crustacea), peas, beans, lentils and 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 natural products. The mean intake of phosphate in the UK diet is 1,260mg/day, and 4.4mg/day from drinking water.(4) The net absorption from a mixed diet has been reported in the range of 55–70% in adults. However, the intestinal absorption of phosphorus is greatest in the jejunum, and decreases along the length of the small intestines. Decreasing dietary phosphate is difficult to achieve without significant reduction in protein intake, which may put patients with renal failure at risk of malnutrition.(5)
In patients on maintenance dialysis, who are usually catabolic, a diet containing 1.0–1.2g/kg/day protein is needed to achieve neutral nitrogen balance. However, such a diet contains approximately 800–1,200mg (20–40mmol) of phosphate. Since the intestinal absorption ranges from 55 to 70% of the ingested phosphate, the amount of absorbed phosphate varies between 11 and 28mmol/day and between 77 and 196mmol/week. This certainly cannot be matched by the decreasing phosphate excretion of the failing kidneys or by the dialytic phosphate removal in patients on maintenance dialysis.(6)
Dialytic phosphate removal
On average, only 500–1,000mg of phosphate is eliminated by one dialysis treatment. The best results are obtained using large-surface-area dialysers with prolonged dialysis times and high blood flow rates. In peritoneal dialysis, the weekly removal of phosphate has been estimated to be approximately 2,200mg, but depends on the distribution of isotonic and hypertonic peritoneal dialysis fluids.(7) Because continuous ambulatory peritoneal dialysis (CAPD) is a continuous daily treatment, the net weekly removal of phosphate is approximately 10% greater than in haemodialysis.(8) However, haemofiltration and haemodialfiltration seem to be more effective than conventional haemodialysis, which is related to the continuous nature of these treatments.(9,10)
Lengthening dialysis or using larger dialysers with higher efficacy enhances phosphate removal; this was demonstrated by the Tassin Centre (Paris, France) experience(11) and by Kooistra and colleagues in the Netherlands.(12) 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 phosphate binders after the fourth month.(13)
Reduced calcium dialysate
Reduction of the dialysis fluid calcium concentration reduces hypercalcaemia in haemodialysis patients without deleterious effects on bone histology.(14) Three independent studies demonstrated these effects in CAPD patients using fluid with a calcium concentration of 1.25mmol/l (instead of 1.75mmol/l).(15–17) Furthermore, the use of a low-calcium dialysate has the advantage of allowing the ingestion of larger doses of calcium and vitamin D, leading to better control of renal bone disease. Extended treatment with low-calcium dialysate may be associated with an increased risk of severe hyperparathyroidism.(18)
Oral phosphate-binding agents
An ideal oral phosphate binder should be nontoxic and acceptable to encourage compliance. In addition, it should have a high affinity for binding phosphorus rapidly with low solubility and systemic absorption. Although a wide range of oral phosphate-binding agents are available (see Table 1), none of them fully satisfies these criteria.(19)
Many studies have demonstrated that both calcium carbonate and calcium acetate are effective at treating hyperphosphataemia in dialysis patients.(20–22) The dose of these binders should be increased gradually until serum phosphate is controlled or adverse effects occur. Hypercalcaemia is the most common problem, but gastrointestinal symptoms (such as change in bowel habit, vague abdominal discomfort and dyspepsia) are often reported. Hypercalcaemia occurs in a substantial percentage of patients taking calcium-containing binders (20–80%),(23,24) and is frequently severe enough to require withdrawal of the binder. Calcium carbonate binds phosphate optimally in an acid environment (pH=5), with the binding capacity being reduced in the neutral pH range.(23) 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.(24) Although the daily intake of calcium is halved in patients who take calcium acetate, the number of hypercalcaemic episodes is comparable.(25) Calcium acetate is capable of binding intestinal phosphate more effectively per mmol of administered elemental calcium than calcium carbonate. Theoretically, 1g of the elemental calcium as the carbonate would bind 43mg of phosphate, whereas 1g of calcium acetate would bind 106mg.(26,27) Long-term adverse effects of calcium-containing phosphate binders are unknown. Tumoural calcinosis and calciphylaxis are a serious concern, and these binders may increase the incidence of such problems.(20)
Calcium alginate has been tested for its capacity as a phosphate binder in vivo and in haemodialysis and CAPD patients.(28) 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 need extra aluminium supplements (placebo or control groups were not included).(29)
Calcium ketoglutarate was compared with calcium carbonate in 32 stable haemodialysis patients (20 receiving calcium ketoglutarate and 12 calcium carbonate). The incidence of severe hypercalcaemia (>2.8mmol/l) was significantly higher in the carbonate group. Moreover, calcium glutarate demonstrated the same phosphate binding potency as calcium carbonate and acetate.(30) However, a high incidence (29%) of gastrointestinal complaints was reported in haemodialysis patients receiving calcium ketoglutarate.(31) The main disadvantage of calcium ketoglutarate is its price, compared with calcium carbonate or acetate. However, in addition to its usefulness in patients prone to hypercalcaemia, it has a putative anabolic effect, which may improve malnutrition in dialysis patients.(32)
Aluminium hydroxide dissolves rapidly and binds phosphate at any pH, making it the most effective phosphate binder in vivo.(33) In patients taking aluminium hydroxide, plasma aluminium levels should be measured monthly. The aluminium toxicity manifestations include osteomalacia, bone and muscle pain, an iron-resistant microcytic anaemia and neurological abnormalities. Bone, brain, heart and liver are major sites of aluminium deposition in the body.(34,35) No safe dose of aluminium hydroxide has been identified, and dialysis patients can develop evidence of aluminium toxicity even at modest doses.(36) Aluminium may be especially toxic in high-risk conditions, such as postparathyroidectomy, diabetes, low turnover bone disease, and following reinstitution of dialysis after kidney transplantation.(37)
Magnesium carbonate was used in 28 patients for 2 years as a substitute for aluminium hydroxide. Serum phosphate was controlled, and patients seemed to tolerate magnesium carbonate well.(38) Studies have confirmed the effectiveness of magnesium salts as binders, but also highlighted significant gastrointestinal side effects. Thus, a magnesium carbonate binder in combination with a low magnesium dialysate is an alternative to calcium-containing binders, although it is not widely used.(38)
Polyuronic acid derivatives, such as sodium ferrous citrate and ferrihydride, have a significant capacity for absorbing phosphorus. They are only slightly soluble in the gastrointestinal tract, preventing excessive uptake of iron, which makes them good candidates for phosphate binding. In a study involving such derivatives, a 20% decrease in serum phosphate, with concomitant decrease in urinary phosphate excretion, was observed; altered bowel habit was the only reported side-effect.(39) The use of crosslinked iron dextran has been reported in haemodialysis patients; an added advantage may certainly result from the small amount of iron absorbed by these often iron-deficient patients. Unfortunately, there is currently little data available for these compounds.(40,41)
Zirconyl chloride octahydrate has been evaluated as a dietary phosphate binder in rats, in which it was as effective as aluminum chloride and reduced bone phosphorus burden significantly.(42) This compound is a potentially promising phosphate binder, although no further development has occurred.
Sevelamer is a water-absorbing, nonabsorbed, hydrogel-crosslinked poly(allylamine hydrochloride) that is free of aluminium and calcium. As a binder, it is at least as effective as calcium acetate but, because of its structure, it also binds certain fat-soluble vitamins, such as 1,25-dihydroxy vitamin D3 and vitamin K.(43) Studies demonstrate a significant reduction in phosphorus levels, with associated decrease in parathyroid hormone (PTH) levels.(44-47) The use of this compound was also associated with lowering serum cholesterol by up to 15% through a mechanism probably similar to that of cholestyramine.(48) Its use is also associated with less coronary and aortic calcification.(49) Sevelamer can be used safely, although diarrhoea (16%) and abdominal pain (13%) were observed in phase III crossover studies.(45) A long-term study confirmed that sevelamer was effective in lowering serum phosphate levels and calcium phosphate product in haemodialyis patients, an effect that was sustained over time.(50) The main disadvantage of this compound is its cost: in 2002, the cost of an average dose of 4,800 mg/day was approximately £2,200 ($3,100, or €3,600).(51) For costs of the different phosphate binders, please see Table 2.
Lanthanum carbonate binds phosphate ionically at all pH values to form lanthanum phosphate, which is highly insoluble.(52) In-vitro studies suggest comparable efficacy to aluminium salts (>97%).(53) The effects of this compound have been studied in over 1,500 haemodialysis and CAPD patients, demonstrating good control of phosphate levels and calcium phosphate products, significantly less than 5.0mmol/l. Low serum lanthanum levels were observed in the majority of patients (0.1–0.8ng/l). This increase was noted for all doses administered versus baseline levels. These levels reached a plateau early in the study and showed no further increase.
Furthermore, they were not dose-dependent, and no pathological or toxic consequences associated with the increase in plasma lanthanum concentrations were reported. The incidence of side-effects was comparable to that observed in the placebo group, and no safety adverse issues were identified.(54) Moreover, bone biopsy results indicate no evidence of direct toxic effects on bone; potentially beneficial changes were observed from adynamic and osteomalacic states to more normal histology after 1 year of treatment.(55)
Although daily nocturnal haemodialysis or short- hours daily dialysis are likely to be suitable for only a minority of home-based patients, these approaches control hyperphosphataemia effectively. However, their use is often limited by logistics and poor acceptance by patients. Controlled studies comparing morbidity, mortality and feasibility of daily dialysis as alternative methods to the more traditional approaches are currently lacking.(56)
Research has recently begun to explore the pathway for possible inhibition of phosphate absorption. The genes responsible for sodium-dependent phosphate transport have now been isolated and characterised. Studies are ongoing to determine whether manipulation of these transporters with novel therapeutic agents might ameliorate the hyperphosphataemia in chronic renal failure. One promising agent is phosphonoformic acid (PFA), a sodium-dependent phosphate transport inhibitor, which has been used effectively in rats. Although the use of PFA in humans is limited by potential toxicity, similar therapeutic agents may prove to be effective.(57,58)
Phosphate control remains a difficult task for nephrologists and, because it is linked with increased cardiac death rates, the importance of achieving this control is paramount. Aluminium-containing binders are still in use, despite the known toxicity of aluminium. The link between calcium-containing binders and coronary and aortic calcification is causing great concern. Moreover, patients with low bone turnover are at increased risk of developing hypercalcaemia, even if the calcium balance is slightly positive.
Sevelamer can achieve effective phosphate control, as well as less coronary and aortic calcification and lower cholesterol levels, and is a good option for patients with long life expectancy and little or no chance of early transplantation. However, gastrointestinal side effects, large dose burden and high cost reduce its usefulness.
Promising new agents in development include polynuclear trivalent iron compounds and lanthanum carbonate. The iron compounds are relatively cheap, and lanthanum carbonate is well tolerated and may have an additional beneficial effect on bone histology.