Renal osteodystrophy: management of hyperphosphataemia

Plasma phosphate concentration, which generally remains normal in early stages of chronic renal failure (CRF), progressively rises in more advanced stages to reach > 3 mM in uncontrolled dialysis patients. The primary mechanism involved is phosphate accumulation in the extracellular space due to insufficient renal elimination, despite a considerable increase in ultrafiltered load at the glomerular level and a marked decrease in tubular reabsorption. Phosphate retention is a potent stimulus to parathyroid hormone (PTH) secretion via indirect and recently discovered direct mechanisms. Hyperphosphataemia thereby contributes to the pathogenesis of secondary hyperparathyroidism and its skeletal expression, namely osteitis fibrosa. In severe forms of parathyroid overfunction, surgical parathyroidectomy is needed. Hyperphosphataemia also promotes, together with calcium, the deposition of calcium phosphate crystals in soft tissues, in particular in the vessel wall and in periarticular regions, with potentially dramatic consequences. The occurrence of such extraskeletal calcifications is favoured by age, secondary hyperparathyroidism and excessive intake of calcium, phosphate (protein) and vitamin D. However, soft-tissue calcium deposits are now observed with increasing frequency in uraemic patients having low to normal serum intact PTH levels, in the setting of adynamic bone disease. It is important to control plasma phosphate early in the course of CRF, in order to avoid or treat secondary hyperparathyroidism and soft-tissue calcifications. There are several ways to achieve this goal: Dietary management in terms of low protein intake has long been shown to be an efficacious means of preventing hyperphosphataemia or of correcting it, and of decreasing the incidence of high-turnover bone disease as a consequence of chronic PTH excess [1]. However, dietetic restrictions are difficult to follow in the long run. Acceptance rate is highly variable, depending greatly on patient cooperation and team motivation. The prescription of various drugs has become the cornerstone of the therapeutic approach of hyperphosphataemia. Orally administered aluminium-containing phosphate binders are highly efficient. Because of the potential danger of aluminium intoxication their use has been abandoned by many clinicians. However, in clinical practice there is often no other choice. Many physicians continue prescribing low doses of aluminium hydroxide, for instance 2–3 g/day. Whether such drugs should still be prescribed at all, in cases of otherwise uncontrollable hyperphosphataemia, remains a matter of lively debate. Orally administered calcium-containing salts are currently the favourite choice. The two most popular preparations are calcium carbonate and calcium acetate [2–8]. Either drug can be given in doses up to 10 g/day. However, a total daily amount of 6 g in two or three divided doses should probably not be exceeded in most instances. Ideally, calcium-containing compounds should be given midway between meals to achieve maximal phosphate binding. The price to pay for phosphate binding by calcium is that large amounts of unbound calcium are absorbed and potentially deposited in soft tissues, especially when plasma phosphate remains elevated. A link between the intake of oral calcium supplements and soft-tissue calcifications has recently been demonstrated [9]. Calcium-containing phosphate binders should not generally be administered together with active vitamin D derivatives because of the even greater risk of extraskeletal calcifications in cases of combined treatment. The administration of calcium citrate to uraemic patients should be avoided, especially if aluminium-containing compounds are given. Calcium citrate favours intestinal aluminium absorption and, hence, aluminium intoxication [10]. A new phosphate binder, sevelamer hydrochloride (Renagel®), which is a non-absorbable polymer devoid of calcium and aluminium, has recently been developed. Its introduction into clinical practice is under way [11,12]. Its phosphate-binding capacity is roughly equivalent to that of calcium carbonate. The daily amount of RenaGel required to maintain plasma phosphate at ⩽1.5 mM was 3 × 880–1760 mg, according to the most recent report published in the literature [12]. This drug offers in addition the advantage that it reduces plasma total cholesterol and low-density lipoprotein (LDL)-cholesterol. The volume of this polymer required to keep plasma phosphate below 1.5 mM is relatively high, so it remains to be seen how many patients are willing to take the large number of capsules required on a day-to-day basis. According to recent information, a more easily acceptable oral form will be marketed in the near future. Other calcium-free and aluminium-free oral phosphate binders are in development, such as stabilized polynuclear iron hydroxide [13]. In the uraemic patient on extra-renal replacement therapy, an intensification of the dialysis procedure leads to a better control of hyperphosphataemia [14]. This can be achieved in several ways. One can increase the membrane surface of the dialyser, for instance from 1m2 to 2 m2, so that dialysis will remove more phosphate. Another, more efficacious, means is to increase dialysis time, either by increasing the length of each session (e.g. from 4 h three times weekly to 5 or 6 h three times weekly), or by switching from the usual three weekly sessions to a greater number of sessions, up to six per week. The much greater efficacy of longer haemodialysis sessions, for instance 8 h three times per week, has been convincingly demonstrated by the Tassin centre experience where chronic haemodialysis patients have normal serum phosphate levels in the absence of any oral chelation therapy [15]. A similarly excellent means of obtaining improved control of serum phosphate, together with a decreased intake of phosphate binder, is the recently proposed daily, short haemodialysis schedule [16]. With overnight daily dialysis, additional oral phosphate must even be given to some patients because of ‘overdialysis’ [17]. In conclusion, hyperphosphataemia is a frequent complication of advanced chronic renal failure, often in association with secondary hyperparathyroidism. It can be prevented or efficaciously treated in many instances, especially if adequate measures are taken early in the course of renal insufficiency and if the patient is cooperative.