Management of Hyperphosphatemia with Calcium‐Based Binders

Patients with advanced end-stage renal disease (ESRD) require control of hyperphosphatemia to help prevent or minimize its complications. These complications include worsening secondary hyperparathyroidism and, in conjunction with hypercalcemia, metastatic calcifications and calciphylaxis. Control of hyperphosphatemia can assist in slowing and reversing the progression of secondary hyperparathyroidism. Animal studies have demonstrated that phosphorus loading via diet results in an increase in serum parathyroid hormone (PTH) and phosphorus level and a decline in serum 1,25-dihydroxycholecalciferol (calcitriol) and calcium levels. This effect was seen not only in animals with advanced renal failure but in animals with mild to moderate renal failure (1–3). The explanation for this observation appears to be the direct stimulative effect of elevated phosphorus levels on PTH secretion (3, 4). Hyperphosphatemia also impedes the effect of calcitriol in reducing PTH levels (5, 6). Thus, to maximize the effect of calcitriol on PTH, the serum phosphorus level should be maintained below 6.0 mg/dL, and preferably below 5.0 mg/dL (7). Metastatic calcification occurs when the calcium phosphorus product rises above 70. Calcification can occur in many organs, including heart, lung, skin, and eyes, and can result in myocardial and valvular dysfunction, cardiac arrhythmias, lung infiltrates, pruritus, and keratitis (8, 9). Patients with metastatic calcifications appear to be at increased risk of calciphylaxis, the calcification of small and medium-sized arteries of the skin that can ultimately result in gangrene. The initial lesion is usually either livedo reticularis or painful mottling of the skin that usually progresses to nonhealing ulcers, often complicated by secondary infection that can lead to sepsis. Lesions usually are found on the distal extremities, but proximal extremity or trunk lesions can be seen, and their presence connotes a poorer prognosis (10, 11). The pathophysiology of calciphylaxis is not entirely known; hence, the treatments for it are unsatisfactory. Some patients improve after parathyroidectomy; however, most patients have a poor prognosis, and the mortality for this disease remains high (12). In the ESRD population, control of serum phosphorus is achieved by a variety of methods, including restricting the intake of dietary phosphorus, removing phosphorus by dialysis, and inhibiting the absorption of phosphorus in the intestine with phosphate binders. The first two methods alone are ineffective for the control of hyperphosphatemia. Phosphorus is ubiquitous in foods containing protein. The recommended protein intake for chronic dialysis patients varies from 1.0–1.2 g/kg/day for hemodialysis patients to 1.2–1.5 g/kg/day for peritoneal dialysis patients. At a protein intake of 1.0 g/kg/day, the average phosphorus intake usually ranges from 900 to 1,200 mg/day, while at a protein intake of 1.4 g/kg/day, the average phosphorus intake usually ranges from 1,700 to 2,400 mg/day (Fig. 1) (13, 14). In ESRD patients, approximately 60%–70% of the ingested phosphorus is absorbed by the gastrointestinal tract (15, 16). The amount of phosphorus removed in a hemodialysis session depends both on the predialysis phosphorus level and on the dose of dialysis delivered; the typical amount of phosphorus removal per session is only 600–700 mg per hemodialysis session (17), but values as high as 1,000 mg per session have been reported (18). Most of the phosphorus is removed during the first 90 min of the dialysis session, as there is a low rate of intercompartmental transfer of this compound (18, 19). In patients receiving continuous ambulatory peritoneal dialysis, the daily removal of phosphorus is approximately 300 mg/day, similar to the daily removal of phosphorus in hemodialysis patients receiving high-efficiency or high-flux hemodialysis three times per week (20). The net positive phosphorus balance seen as a result of typical dietary intake and with removal of phosphorus by hemodialysis will range from a low of 240 mg/day to a high of 600 mg/day (see Fig. 1). Therefore, the necessary third element in the control of serum phosphorus levels is the use of phosphate binders. The first practical phosphate binders were aluminumbased compounds. Although these agents were highly effective in reducing serum phosphorus levels in patients with ESRD, such side effects as dialysis encephalopathy, Address correspondence to: Michael V. Rocco, MD, Wake Forest University School of Medicine, Section on Nephrology, Medical Center Boulevard, Winston-Salem, NC 27157– 1053. E-mail: mrocco@wfubmc.edu. Seminars in Dialysis—Vol 12, No 3 (May–June) 1999 pp. 195–201