Nephrol Dial Transplant (2002) 17: 1170–1175

Invited Comment

Management of hyperphosphataemia of chronic kidney disease: lessons from the past and future directions Hartmut H. Malluche and Hanna Mawad University of Kentucky, Division of Nephrology, Bone and Mineral Metabolism, Lexington, KT 40536-0084, USA

Abstract A historical look at research in hyperphosphataemia of chronic kidney disease over the last 40 years shows remarkable advances in our understanding of this abnormality and in the technology used to manage it. Phosphate binders, which have become a mainstay in the management of hyperphosphataemia, have evolved from the early use of aluminium gels to calcium salts, to novel, non-absorbed, aluminium-free, calciumfree agents such as sevelamer hydrochloride, and to magnesium-, iron-, and lanthanum-based compounds. With recent advances, clinical management of this complication of chronic renal disease is evolving from adequate care to optimal care, such that new standards in phosphorous management are being set, and various parameters of patient care are being integrated to optimize outcomes and minimize side effects. This paper provides a historical view of the clinical management of hyperphosphataemia, and looks to advances in treatment that are changing the course of renal bone disease management. Keywords: aluminium; hyperphosphataemia; lanthanum; magnesium; renal bone disease; sevelamer hydrochloride

Introduction Since the discovery that kidney disease impairs mineral metabolism, the search for an ideal phosphate binder has been an important goal in the management of renal bone disease. Control of blood phosphate levels using phosphate binders made possible the alleviation of several complications of end-stage renal disease (ESRD), including secondary hyperparathyroidism and bone disorders. At the same time,

Correspondence and offprint requests to: Prof. Dr Hartmut H. Malluche, University of Kentucky, Division of Nephrology, Bone and Mineral Metabolism, 800 Rose Street, Room MN 564, Lexington, KY 40536-0084, USA. Email: [email protected] #

managing hyperphosphataemia has involved clinical trade-offs that expose the limitations of available therapies and our knowledge of the disease. Aluminium-based binders were first used in the 1970s due to their efficient binding to phosphate and because it was assumed that aluminium was poorly absorbed from the gut. Later, aluminium became a cautionary tale in medicine because the metal was found to accumulate in the body and cause severe bone and brain disorders [1–3]. Widespread use of calcium-based phosphate binders in the 1980s, as a replacement for aluminium, shows important parallels with respect to their use as a tool in nephrology. Although calcium salts are viewed as relatively benign and efficient binders of phosphate, ingestion of large amounts of calcium agents resulting in a large positive calcium balance has been increasingly associated with hypercalcaemia, progressive metastatic calcification and adynamic bone disorders [4 –9]. Limitations of calcium-based binders have driven the development of calcium-free, aluminium-free phosphate binders. The non-absorbed polymer sevelamer hydrochloride has been used successfully for several years and has changed the standards for phosphorous management. While currently not in widespread clinical use, magnesium, lanthanum, and other aluminiumfree agents also have been studied experimentally as alternative phosphate binders in dialysis patients.

Management of serum phosphorous and renal bone disease: a historical view Role of calcium balance and phosphorous retention Since the discovery that declining serum calcium levels trigger secretion of parathyroid hormone (PTH), research in the 1970s focused on the role of hypocalcaemia and phosphorous retention in the development of secondary hyperparathyroidism (SHPT) and renal osteodystrophy (ROD). Early studies by Slatopolsky et al. [10] in uraemic dogs implicated transient hypocalcaemia, caused in part by phosphorous

2002 European Renal Association–European Dialysis and Transplant Association

Management of hyperphosphataemia of chronic kidney disease

retention, in the oversecretion of PTH. These studies showed that restricting phosphorous intake in proportion to decreases in the glomerular filtration rate prevented SHPT [10,11]. Similarly, Goldsmith et al. [12] showed that PTH secretion could be suppressed by calcium infusions in haemodialysis patients, implicating a role of calcium in the pathogenesis and management of SHPT. These important early studies led to greater understanding of the prevention and management of SHPT and ROD. Correction of hypocalcaemia through calcium and calcitriol supplementation, dietary restriction of phosphorous, and the use of aluminium as an early phosphate binder became essential strategies in the treatment of patients with renal disease [13,14]. Focus on hyperphosphataemia and calcium-based phosphate binders In the 1970s and 1980s, concerns about aluminium toxicity led to a gradual decline in the use of aluminiumbased phosphate binders. Although the potential pathological consequences of aluminium were raised early on [1,15,16], this agent continued to be used as the primary binder until alternatives became clinically available. From a chemical standpoint, aluminiumbased binders were appealing because of their ability to form tight, insoluble complexes with phosphate; however, aluminium ingested in large doses over an extended time period was found to be absorbed. Since the kidney is the primary route of aluminium excretion, loss of renal function compromised the ability of patients with renal failure to handle an extra aluminium load; the uraemic state and acid-containing compounds enhanced absorption and retention of aluminium to toxic levels [16]. Patients receiving long-term therapy with aluminium-based binders were eventually recognized to be at risk for encephalopathy and bone disease associated with elevated aluminium levels in brain and bone tissue [1–3]. Aluminium-related bone disease is characterized by low-turnover osteomalacia and adynamic bone disease, and results in painful, disabling pathological fractures that may be accompanied by myopathy [2,3,9]. Recognition of these serious side effects prompted the search for aluminium-free phosphate binders. Calcium carbonate, calcium acetate and magnesium salts were studied as alternative binders [17–19]. Calcium-based binders largely replaced aluminiumbased binders in the 1980s and 1990s, although aluminium was still used in a subset of patients. While not as efficient as aluminium, calcium-based binders effectively bind phosphorous in the intestine, limiting its absorption. Consequently, calcium-based binders were viewed as safer alternatives to aluminium. However, effective binding of dietary phosphate requires large daily doses of calcium, often enough to induce hypercalcaemia and positive calcium balance. Coadministration of calcitriol to control SHPT further enhances calcium absorption. Moreover,

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calcium-based binders are frequently not well tolerated by patients, and patient adherence to the calciumbased binder regimen is poor. Furthermore, elevations in calcium 3 phosphorous (Ca 3 P) product are common with calcium-based binders. Impacts of hyperphosphataemia and positive calcium balance The health risks associated with elevated Ca 3 P product and hyperphosphataemia have been well documented in the last decade and have become an important basis for changes in clinical management of hyperphosphataemia and the establishment of new clinical standards. Several investigators have demonstrated a direct role of hyperphosphataemia in the development of PTH oversecretion, parathyroid hyperplasia and resistance to vitamin D therapy [20–22]. Further, an important epidemiological study in 1998 found that hyperphosphataemia and Ca 3 P product )55 mgudl significantly increased the risk of mortality, suggesting that clinical strategies and standards in place in the 1990s had limited effectiveness, and put patients at greater risk of complications and death [23]. The role of elevated Ca 3 P product and positive calcium balance in the development of metastatic calcification, in particular cardiac calcification and complications, is currently an area of tremendous interest [4–7,24,25]. Cardiac risk is dramatically increased in dialysis patients, who have a 30 times greater risk of cardiovascular death as compared with the general population [26]. Elevated Ca 3 P product and hyperphosphataemia are viewed as important risk factors for cardiac and metastatic calcification, conditions that may predispose patients to cardiac complications and death [6,7,23,25]. Many recent studies indicate that cardiac calcification is common and progressive in the dialysis population [4–7]. In a 1996 study by Braun et al. [4], mitral valve and aortic valve calcifications were observed in 59% and 55% of dialysis patients, respectively, as assessed by electron beam computed tomography (EBCT). Other researchers reported a greater prevalence of cardiac valve calcification in dialysis patients as compared with normal patients [7], and elevated Ca 3 P product was positively correlated to the presence of calcification. A recent study by Goodman et al. [6] using EBCT found that coronary artery calcification was common in young adult haemodialysis patients. Ca 3 P product and intake of calcium-containing binders were higher among patients with cardiac calcification. These studies represent an important shift in nephrology, as researchers focus on understanding the causes of calcification and elevated Ca 3 P product, and minimizing the risk of cardiac death in the dialysis population. Similarly, interest has grown in understanding the role of positive calcium balance in the development and prevalence of low turnover bone disorders. While aluminium-related bone disease has declined significantly, adynamic forms of the disease have emerged in

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the last decade [27–30]. Daily ingestion of calciumbased binders, use of vitamin D therapy, changes in PTH management and other treatment factors may be important parameters related to this shift [28,31]. These emerging trends in renal bone disease, reflected in changes in clinical tools and practices, have prompted focus on new strategies that more effectively control serum phosphorous and minimize impacts on calcium and bone metabolism.

H. H. Malluche and H. Mawad

Benefits of sevelamer treatment also appeared to translate into a lower risk of hospitalization and medical care costs as compared with conventional phosphate binder therapy, based on a case-control study of Medicare patients [35]. These positive studies indicate the important role of sevelamer in the treatment of hyperphosphataemia and renal bone disease. Use of magnesium

New approaches and future directions Development of calcium-free, aluminium-free phosphate binders Concerns about the toxic effects of aluminium and limitations of calcium-based binders have fuelled interest in alternative, calcium-free, aluminium-free phosphate binders. Sevelamer hydrochloride is an important advance because it is not absorbed and does not impact serum calcium levels [32,33]. Other phosphate binders of interest currently under investigation include magnesium compounds, lanthanum salts and other agents. Sevelamer hydrochloride Sevelamer hydrochloride (Renagel1, Genzyme Therapeutics, Cambridge, MA, USA) is a calciumfree, aluminium-free phosphate binder approved by the U.S. Food and Drug Administration in 1998. Since that time, various clinical studies have demonstrated the ability of sevelamer to control serum phosphorous and Ca 3 P product in dialysis patients, with minimal impact on serum calcium levels and a low incidence of side effects [32,33]. In phase III crossover studies in haemodialysis patients, sevelamer treatment decreased serum phosphorous levels to similar levels after 8 weeks, as compared with calcium acetate treatment (mean change of 2.0"2.3 mgudl vs 2.1"1.9 mgudl, respectively) [34]. With equipotent phosphorous control, Ca 3 P product was lower and iPTH levels were less suppressed. Hypercalcaemia ()11.0 mgudl) occurred in 5% of patients during sevelamer treatment, as compared with 22% of patients receiving calcium acetate (P-0.0001) [34]. Long-term treatment with sevelamer resulted in sustained reductions in serum phosphorous and Ca 3 P product. In an open-label clinical trial of 192 haemodialysis patients, sevelamer treatment was associated with a mean change in serum phosphorous levels of 0.71"0.77 mmolul and a mean change in Ca 3 P product of 1.46"1.78 mmol2ul2 after 44 weeks [33]. Positive changes in blood lipids also occurred during treatment, as low density lipoprotein decreased by an average of 30% from baseline (mean change 0.82"0.74 mmolul, P-0.0001), and high density lipoprotein levels increased from baseline by an average of 18% (mean change 0.15"0.29 mmolul, P-0.0001) [33].

Magnesium has been used experimentally in recent decades as an adjunct or alternative to calcium-based phosphate binders. Early studies by Guillot et al. [36] investigated magnesium hydroxide as a phosphate binder in nine patients with ESRD on haemodialysis. Using doses of 0.75 to 3 g of Mg(OH)2 per day for 3–5 weeks and dialysate magnesium concentrations of 1.2 to 1.8 mgudl, serum phosphorous concentrations decreased from 9.0 mgudl (2.9 mmolul) during the control period to 8.1 mgudl (2.6 mmolul) after treatment, indicating inadequate control in this short-term study. A similar study by Oe et al. [37] involved switching 18 haemodialysis patients from aluminium hydroxide to magnesium hydroxide in combination with magnesium-free dialysate. These researchers found that magnesium doses of 2.4 to 2.6 guday for up to 13 weeks were unable to adequately control serum phosphate levels, and side effects such as diarrhoea and hypermagnesaemia limited increasing the dose further. O’Donovan et al. [38] reported more positive results with the use of magnesium carbonate and magnesiumfree dialysate in 28 haemodialysis patients switching from aluminium hydroxide in a 2-year study. Control of serum phosphate was effective, based on magnesium doses of 155–465 mguday [38]. In a 10 week, prospective, randomized crossover study of 15 haemodialysis patients, Delmez et al. [39] found that magnesium carbonate at doses of 465"52 mguday of elemental magnesium, in combination with a dialysate magnesium concentration of 0.6 mgudl, lowered the required calcium carbonate dose and allowed higher calcitriol doses to be used. Mean serum phosphate levels were similar during the magnesium carbonateucalcium carbonate combination treatment as compared with calcium carbonate treatment alone (5.7"0.2 mgudl vs 5.2"0.2 mgudl, respectively). No adverse gastrointestinal effects were reported in this study. Because use of magnesium-based binders requires reduced magnesium dialysate, and because these binders must be used at relatively high doses and are absorbed in the intestine like calcium salts, side effects are common. These include diarrhoea, hyperkalaemia [37,40], and hypermagnesaemia [41], which may contribute to inhibition of bone mineralization and exert suppressive effects on the CNS. MagneBind1 (Nephro-Tech, Inc., Shawnee, KS, USA), a binding agent containing magnesium carbonate and calcium carbonate, is commercially available as a dietary supplement; however, the safety and efficacy of this agent as a phosphate binder has

Management of hyperphosphataemia of chronic kidney disease

not been evaluated by the U.S. Food and Drug Administration. Use of lanthanum salts Lanthanum, a rare earth metal, is found in trace amounts in the body. Lanthanum cations bind phosphate anions to form an insoluble salt that is poorly absorbed by the gastrointestinal tract. For this reason, lanthanum has been studied as an aluminiumfree phosphate binder. Graff et al. [42] first reported the use of lanthanum chloride hydrate as a phosphate binder in rats. Lanthanum treatment decreased total plasma phosphate concentrations and urinary phosphorous excretion, comparable to aluminium chloride treatment. No toxic effects were noted in this study; however, in an additional long-term study of 100 days, the researchers reported marked lanthanum concentrations in liver, lungs and other tissues of treated rats as compared with controls (P-0.01), indicating that this lanthanum salt is absorbed by the gastrointestinal tract and accumulates in tissues [42]. Lanthanum carbonate is being investigated as a potential alternative phosphate binder because it is much less soluble than lanthanum chloride. Lanthanum carbonate (Shire Pharmaceuticals, Rockville, MD, USA) has undergone phase I and phase II clinical trials and is now in phase III trials in the US and Europe. In toxicity studies in rats and dogs, lanthanum carbonate doses of 2 gukg of body weight appeared safe after 3 months of treatment [43]. Hutchinson et al. [43] reported results of phase I studies in healthy male volunteers, in which multiple lanthanum carbonate doses of up to 4.5 guday decreased urinary phosphate excretion significantly compared with baseline levels over the course of 3 days and was well tolerated. Final results from phase II studies of lanthanum carbonate have not yet been reported; however, preliminary results were presented from randomized, placebo-controlled trials that examined the safety and efficacy of lanthanum carbonate in 145 ESRD patients [44,45]. Daily doses of 1350 and 2250 mg of lanthanum carbonate resulted in significant reductions in serum phosphate after 6 weeks (P-0.05). No differences in adverse effects between treatment and placebo groups were found, other than a slight increase in the incidence of gastrointestinal complaints [44,45]. These results indicate that lanthanum carbonate may be an effective binder in dialysis patients. Longterm safety studies, however, have not been reported. It is not known, for example, to what extent lanthanum carbonate administered in large doses over an extended time period can be absorbed by the human gastrointestinal tract and accumulate in body tissues, or whether the uraemic state may enhance absorption or accumulation of the compound in humans. Lanthanum has been shown to be incorporated in bones and teeth, possibly via exchange of lanthanum for calcium in the mineral matrix [46]. In a rat model of chronic renal failure, recent studies demonstrated a dose-dependent accumulation

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of lanthanum in bone following 12 weeks of orally administered lanthanum carbonate [47]. Lanthanum accumulation was associated with a dose-dependent increase in osteoid area, as well as a decrease in the rate of bone formation, suggesting that intestinal absorption of lanthanum carbonate and accumulation of this rare earth metal within bone may lead to mineralization defects and osteomalacia [47]. However, these abnormalities are most probably related to phosphorous deprivation since similar histological findings were found in rats treated with the non-absorbable sevelamer inducing similar lowering of serum phosphorous. Toxic effects of lanthanum have been reported in other in vitro and animal studies [48–50]. Thus, the long-term safety of lanthanum agents in humans needs to be established.

New standards in phosphorous management Requirements of an optimal phosphate binder New calcium-free, aluminium-free phosphate binders that effectively bind phosphorous and have low incidence of side effects are building on our knowledge of renal bone disease. Consensus is forming on the characteristics of an optimal phosphate binder, and improved guidelines for the clinical management of hyperphosphataemia and SHPT. The ideal phosphate binder should be safe and well tolerated, palatable, non-absorbable or excretable anduor dialysable, costeffective, and have good efficacy and specificity. Furthermore, it should not add to the aluminium burden nor should it contribute to an excessive calcium load or accumulate in bone or other vital organs, causing organ dysfunction. On the basis of clinical studies over the last few years, sevelamer hydrochloride appears to meet the requirements of an ideal binder and has raised the standard for phosphate management in renal patients. Further research is needed on other experimental phosphate binders to ensure that they are safe and effective.

Balanced approach to managing renal bone disease An important next step in the management of renal bone disease is to integrate fully advances in phosphate binder therapy with optimal bone, PTH and cardiac health care. Various investigators have called for new treatment goals of serum phosphorous and calcium to near normal values and a Ca 3 P product -55 [51–54]. In addition, the use of non-calcaemic vitamin D analogues, more adequate assessment of bone turnover and PTH status [55,56], and regular monitoring and assessment of cardiac health through EBCT and other tools [25] are important strategies that will advance patient care. Prevention of metastatic calcification and cardiac death are of utmost importance in the management of hyperphosphataemia and elevated PTH. These

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strategies may significantly improve patient survival and lower the risk of disease complications in the dialysis population.

Conclusions As our understanding of renal bone disease has grown, so too has our ability to manage consequences of the disorder and extend patient lives. Building on advances and lessons of the past, nephrologists now have more effective, sophisticated tools available to treat renal disease that help replace renal function while minimizing complications and side effects. Phosphate binders have been an indispensable tool in the management of patients, and novel, calcium-free, aluminium-free agents are important advances that have raised the standards in phosphorous management. Clinical strategies that effectively control renal bone disease to maintain the important role of bone in mineral homeostasis are called for. They include optimizing control of phosphorous, calcium, PTH, calcitriol, and bone and cardiac health. This will continue to improve patient outcomes and advance the course of nephrology. Acknowledgement. Writing of this editorial was sponsored by an unrestricted educational grant from Genzyme Corporation.

References 1. Alfrey AC, LeGendre GR, Kaehny WD. The dialysis encephalopathy syndrome. Possible aluminum intoxication. N Engl J Med 1976; 294: 184–188 2. Malluche HH, Faugere MC. Aluminum-related bone disease. Blood Purif 1988; 6: 1–15 3. Kerr DN, Ward MK, Arze RS et al. Aluminum-induced dialysis osteodystrophy: the demise of ‘Newcastle bone disease’? Kidney Int 1986; 18: S58–S64 4. Braun J, Oldendorf M, Moshage W, Heidler R, Zeitler E, Luft FC. Electron beam computed tomography in the evaluation of cardiac calcifications in chronic dialysis patients. Am J Kidney Dis 1996; 27: 394–401 5. Hu¨ting J. Mitral valve calcification as an index of left ventricular dysfunction in patients with end-stage renal disease on peritoneal dialysis. Chest 1994; 105: 383–388 6. Goodman WG, Goldin J, Kuizon BD et al. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 2000; 342: 1478–1483 7. Ribeiro S, Ramos A, Brandao A et al. Cardiac valve calcification in hemodialysis patients: role of calcium-phosphate metabolism. Nephrol Dial Transplant 1998; 13: 2037–2040 8. Raggi P, Burke SK, Dillon MA, Amin N, Bommer J, Chertow GM. Sevelamer attenuates the progression of coronary and aortic calcification compared with calcium-based phosphate binders [Abstract]. J Am Soc Nephrol 2001; 12: 239A 9. Malluche HH, Monier-Faugere MC. Risk of adynamic bone disease in dialyzed patients. Kidney Int Suppl 1992; 38: S62–S67 10. Slatopolsky E, Bricker NS. The role of phosphorus restriction in the prevention of secondary hyperparathyroidism in chronic renal disease. Kidney Int 1973; 4: 141–145 11. Slatopolsky E, Caglar S, Gradowska L, Canterbury J, Reiss E, Bricker NS. On the prevention of secondary hyperparathyroidism in experimental chronic renal disease using ‘proportional reduction’ of dietary phosphorus intake. Kidney Int 1972; 2: 147–151

H. H. Malluche and H. Mawad 12. Goldsmith RS, Furszyfer J, Johnson WJ, Fournier AE, Sizemore GW, Arnaud CD. Etiology of hyperparathyroidism and bone disease during chronic hemodialysis. 3. Evaluation of parathyroid suppressibility. J Clin Invest 1973; 52: 173–180 13. Rutherford E, Mercado A, Hruska K et al. An evaluation of a new and effective phosphorus binding agent. Trans Am Soc Artif Intern Organs 1973; 19: 446–449 14. Slatopolsky E, Rutherford WE, Rosenbaum R, Martin K, Hruska K. Hyperphosphatemia. Clin Nephrol 1977; 7: 138–146 15. Berlyne GM, Ben-Ari J, Pest D et al. Hyperaluminaemia from aluminum resins in renal failure. Lancet 1970; 2: 494–496 16. Marsden SN, Parkinson IS, Ward MK, Ellis HA, Kerr DN. Evidence for aluminum accumulation in renal failure. Proc Eur Dial Transplant Assoc 1979; 16: 588–596 17. Mai ML, Emmett M, Sheikh MS, Santa Ana CA, Schiller L, Fordtran JS. Calcium acetate, an effective phosphorus binder in patients with renal failure. Kidney Int 1989; 36: 690–695 18. Hercz G, Kraut JA, Andress DA et al. Use of calcium carbonate as a phosphate binder in dialysis patients. Miner Electrolyte Metab 1986; 12: 314–319 19. Slatopolsky E, Weerts C, Stokes T, Windus D, Delmez J. Alternative phosphate binders in dialysis patients: calcium carbonate. Semin Nephrol 1986; 6: 35–41 20. Slatopolsky E, Delmez JA. Pathogenesis of secondary hyperparathyroidism. Am J Kidney Dis 1994; 23: 229–236 21. Naveh-Many T, Rahamimov R, Livini N, Silver J. Parathyroid cell proliferation in normal and chronic renal failure rats: the effects of calcium, phosphate and vitamin D. J Clin Invest 1995; 96: 1786–1793 22. Almaden Y, Hernandez A, Torregrosa V et al. High phosphate level directly stimulates parathyroid hormone secretion and synthesis by human parathyroid tissue in vitro. J Am Soc Nephrol 1998; 9: 1845–1852 23. Block GA, Hulbert-Shearon TE, Levin NW, Port FK. Association of serum phosphorus and calcium 3 phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis 1998; 31: 607–617 24. Hsu C. Are we mismanaging calcium and phosphate metabolism in renal failure? Am J Kidney Dis 1997; 29: 641–649 25. Raggi P. Detection and quantification of cardiovascular calcifications with electron beam tomography to estimate risk in hemodialysis patients. Clin Nephrol 2000; 54: 325–333 26. Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 1998; 32: S112–S119 27. Monier-Faugere MC, Malluche HH. Trends in renal osteodystrophy: a survey from 1983 to 1995 in a total of 2248 patients. Nephrol Dial Transplant 1996; 11: 111–120 28. Pei Y, Hercz G, Greenwood C et al. Risk factors for renal osteodystrophy: a multivariant analysis. J Bone Miner Res 1995; 10: 149–156 29. Malluche H, Faugere MC. Renal bone disease 1990: an unmet challenge for the nephrologist. Kidney Int 1990; 38: 193–211 30. Sherrard DJ, Hercz G, Pei Y et al. The spectrum of bone disease in end-stage renal failure—an evolving disorder. Kidney Int 1993; 43: 436–442 31. Kurz P, Monier-Faugere MC, Bognar B et al. Evidence for abnormal calcium homeostasis in patients with adynamic bone disease. Kidney Int 1994; 46: 855–861 32. Slatopolsky EA, Burke SK, Dillon MA. RenaGel, a nonabsorbed calcium- and aluminum-free phosphate binder, lowers serum phosphorus and parathyroid hormone. The RenaGel Study Group. Kidney Int 1999; 55: 299–307 33. Chertow GM, Burke SK, Dillon MA, Slatopolsky E. Long-term effects of sevelamer hydrochloride on the calcium 3 phosphate product and lipid profile of haemodialysis patients. Nephrol Dial Transplant 1999; 14: 2907–2914 34. Bleyer AJ, Burke SK, Dillon M et al. A comparison of the calcium-free phosphate binder sevelamer hydrochloride with calcium acetate in the treatment of hyperphosphatemia in hemodialysis patients. Am J Kidney Dis 1999; 33: 694–701 35. Collins AJ, St Peter WL, Dalleska FW, Ebben JP, Ma JZ. Hospitalization risks between Renagel phosphate binder treated and non-Renagel treated patients. Clin Nephrol 2000; 54: 334–341

Management of hyperphosphataemia of chronic kidney disease 36. Guillot AP, Hood VL, Runge CF, Gennari FJ. The use of magnesium-containing phosphate binders in patients with endstage renal disease on maintenance hemodialysis. Nephron 1982; 30: 114–117 37. Oe PL, Lips P, van der Meulen J, de Vries PM, van Bronswijk H, Donker AJ. Long-term use of magnesium hydroxide as a phosphate binder in patients on hemodialysis. Clin Nephrol 1987; 28: 180–185 38. O’Donovan R, Baldwin D, Hammer M, Moniz C, Parsons V. Substitution of aluminium salts by magnesium salts in control of dialysis hyperphosphataemia. Lancet 1986; 1: 880–882 39. Delmez JA, Kelber J, Norword KY, Giles KS, Slatopolsky E. Magnesium carbonate as a phosphorus binder: a prospective, controlled, crossover study. Kidney Int 1996; 49: 163–167 40. Moriniere P, Vinatier I, Westeel PF et al. Magnesium hydroxide as a complementary aluminium-free phosphate binder to moderate doses of oral calcium in uraemic patients on chronic haemodialysis: lack of deleterious effect on bone mineralisation. Nephrol Dial Transplant 1988; 3: 651–656 41. Gonella M, Ballanti P, Della Rocca C et al. Improved bone morphology by normalizing serum magnesium in chronically hemodialyzed patients. Miner Electrolyte Metab 1988; 14: 240–245 42. Graff L, Burnel D. A possible non-aluminum oral phosphate binder? A comparative study on dietary phosphorus absorption. Res Commun Mol Pathol Pharmacol 1995; 89: 373–388 43. Hutchinson AJ. Calcitriol, lanthanum carbonate and other phosphate binders in the management of renal osteodystrophy. Perit Dial Int 1999; 19 [Suppl 2]: S408–S412 44. Joy MS, Hladik GA, Finn WF. Safety of an investigational phosphate binder (lanthanum carbonate) in hemodialysis patients [Abstract]. J Am Soc Nephrol 1999; 10: A1327 45. Finn WF, Joy MS, Hladik GA. Results of a randomized doseranging, placebo controlled study of lanthanum carbonate for reduction of serum phosphate in chronic renal failure patients receiving hemodialysis [Abstract]. J Am Soc Nephrol 1999; 10: A1317

1175 46. Fernandez-Gavarron F, Huque T, Rabinowitz JL, Brand JG. Incorporation of 140-lanthanum into bones, teeth and hydroxyapatite. Bone Miner 1988; 3: 283–291 47. Behets GJ, Dams G, Damment S, D’Haese PC, De Broe ME. An assessment of the effects of lanthanum on bone in a chronic renal failure (CRF) rat model [Abstract]. American Society of Nephrology Meeting 2001, San Francisco, CA: A3862 48. Palmer RJ, Butenhoff JL, Stevens JB. Cytotoxicity of the rare earth metals cerium, lanthanum and neodymium in vitro: comparisons with cadmium in a pulmonary macrophage primary culture system. Environ Res 1987; 43: 142–156 49. Basu A, Chakrabarty K, Chatterjee GC. Neurotoxicity of lanthanum chloride in newborn chicks. Toxicol Lett 1982; 14: 21–25 50. Das T, Sharma A, Talukder G. Effects of lanthanum in cellular systems. A review. Biol Trace Elem Res 1988; 18: 201–228 51. Block GA. Prevalence and clinical consequences of elevated Ca 3 P product in hemodialysis patients. Clin Nephrol 2000; 54: 318–324 52. Block GA, Port FK. Re-evaluation of risks associated with hyperphosphatemia and hyperparathyroidism in dialysis patients: recommendations for a change in management. Am J Kidney Dis 2000; 35: 1226–1237 53. Malluche HH, Monier-Faugere MC. Understanding and managing hyperphosphatemia in patients with chronic renal disease. Clin Nephrol 1999; 52: 267–277 54. Norris KC. Toward a new treatment paradigm for hyperphosphatemia in chronic renal disease. Dial Transplant 1998; 27: 767–772 55. Malluche HH, Langub MC, Monier-Faugere MC. The role of bone biopsy in clinical practice and research. Kidney Int Suppl 1999; 73: S20–S25 56. Monier-Faugere M-C, Geng Z, Mawad H et al. Improved assessment of bone turnover by the PTH-(1–84)ularge C-PTH fragments ratio in ESRD patients. Kidney Int 2001; 60: 1460–1468