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, calcium-free 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, 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 [13].
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 [49].
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 aluminium-free 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 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 aluminium-based 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, aluminium-based 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 [13]. 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 [1719]. Calcium-based binders largely replaced aluminium-based 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, calcium-based binders are frequently not well tolerated by patients, and patient adherence to the calcium-based binder regimen is poor. Furthermore, elevations in calciumxphosphorous (CaxP) product are common with calcium-based binders.
Impacts of hyperphosphataemia and positive calcium balance
The health risks associated with elevated CaxP 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 [2022]. Further, an important epidemiological study in 1998 found that hyperphosphataemia and CaxP product >55 mg/dl 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 CaxP product and positive calcium balance in the development of metastatic calcification, in particular cardiac calcification and complications, is currently an area of tremendous interest [47,24,25]. 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 CaxP 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 [47]. 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 CaxP 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. CaxP 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 CaxP 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 the last decade [2730]. Daily ingestion of calcium-based 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.
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 (Renagel®, Genzyme Therapeutics, Cambridge, MA, USA) is a calcium-free, 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 CaxP 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 mg/dl vs -2.1±1.9 mg/dl, respectively) [34]. With equipotent phosphorous control, CaxP product was lower and iPTH levels were less suppressed. Hypercalcaemia (>11.0 mg/dl) 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 CaxP 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 mmol/l and a mean change in CaxP product of -1.46±1.78 mmol2/l2 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 mmol/l, P<0.0001), and high density lipoprotein levels increased from baseline by an average of 18% (mean change 0.15±0.29 mmol/l, P<0.0001) [33].
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
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 35 weeks and dialysate magnesium concentrations of 1.2 to 1.8 mg/dl, serum phosphorous concentrations decreased from 9.0 mg/dl (2.9 mmol/l) during the control period to 8.1 mg/dl (2.6 mmol/l) 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 g/day 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 magnesium-free 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 155465 mg/day [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 mg/day of elemental magnesium, in combination with a dialysate magnesium concentration of 0.6 mg/dl, lowered the required calcium carbonate dose and allowed higher calcitriol doses to be used. Mean serum phosphate levels were similar during the magnesium carbonate/calcium carbonate combination treatment as compared with calcium carbonate treatment alone (5.7±0.2 mg/dl vs 5.2±0.2 mg/dl, 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. MagneBind® (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 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 aluminium-free 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 g/kg 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 g/day 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. Long-term 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 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 [4850]. 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 and/or dialysable, cost-effective, 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 CaxP product <55 [5154]. 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 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.
Acknowledgments
Writing of this editorial was sponsored by an unrestricted educational grant from Genzyme Corporation.
Notes
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: hhmall{at}uky.edu
References