Oral phosphate binders

Transcription

1 translational nephrology & 2009 International Society of Nephrology Oral phosphate binders Alastair J. Hutchison 1 1 Manchester Institute of Nephrology and Transplantation, The Royal Infirmary, Manchester, UK Hyperphosphatemia is an inevitable consequence of endstage chronic kidney disease and is present in the majority of dialysis patients. Hyperphosphatemia is observationally and statistically associated with increased cardiovascular mortality among dialysis patients. Dietary restriction of phosphate and current dialysis modalities are not sufficiently effective to maintain serum phosphate levels within the recommended range, so the majority of dialysis patients require oral phosphate binders. However, the benefits of achieving the recommended range have yet to be shown prospectively. Unfortunately, conventional phosphate binders are not reliably effective and are associated with a range of limitations and. Aluminum-containing agents are highly efficient but no longer widely used because of proven toxicity. Calcium-based salts are inexpensive, effective, and most widely used, but there is now concern about their association with hypercalcemia and vascular calcification. Sevelamer hydrochloride is associated with fewer adverse effects, but a large pill burden and high cost are limiting factors to its wider use. Lanthanum carbonate is another non-aluminum, calcium-free phosphate binder. Preclinical and clinical studies have shown a good safety profile, and it appears to be well tolerated and effective in reducing phosphate levels in dialysis patients; however, it is similarly expensive. Data on its safety profile over 6 years of treatment are now published. Achievement of opinion-based guidelines appears to have become an end in itself. Dialysis patient outcomes are worse than outcomes for many types of cancer, yet prospective, outcome-based randomized controlled trials are not being undertaken for reasons that are difficult to explain. Kidney International (2009) 75, ; doi: /ki ; published online 11 March 2009 KEYWORDS: calcium; hyperphosphatemia; lanthanum carbonate; phosphate binders; renal dialysis; sevelamer Correspondence: Alastair J. Hutchison, Manchester Institute of Nephrology and Transplantation, The Royal Infirmary, Oxford Road, Manchester M13 9WL, UK. alastair.hutchison@cmft.nhs.uk Received 23 October 2008; revised 18 December 2008; accepted 13 January 2009; published online 11 March 2009 Normal kidneys filter large amounts of organic phosphate of which more than 90% is reabsorbed by the renal tubules. Early renal dysfunction not only reduces filtered phosphate but also decreases tubular resorption, so that urinary phosphate excretion continues to match gastrointestinal absorption, and therefore there is little change in serum phosphate levels. However, as renal function deteriorates further, this homeostatic mechanism fails, resulting in progressive hyperphosphatemia. Despite the absence of interventional randomized controlled trials (RCTs) of phosphate lowering in patients with chronic kidney disease (CKD), phosphate is now regarded as a uremic toxin. 1 The demonstration of a statistical association between serum phosphate and all-cause mortality in patients on dialysis 2 has transformed the phosphate molecule from a subject of little interest 10 years ago to dialysis enemy number 1 today. Unfortunately, there is little evidence that phosphate control has improved significantly over the past decade, despite the development of numerous oral phosphate binders. Several factors may have contributed to this, including the difficulty of adhering to low phosphate diets and oral phosphate binder prescriptions, on a background of inadequate phosphate clearance by dialysis. Other factors such as efficacy, cost, palatability, and safety of available binders are also important (Table 1). Despite greater interest in serum phosphate, control remains poor, so that more than 36% of UK hemodialysis patients have plasma phosphate greater than 1.8 mmol/l. 3 Of equal concern is the fact that there is no evidence from RCTs that reducing serum phosphate to a specific level results in improved clinical outcomes largely because the appropriate trials have not been undertaken. 4 WHY SHOULD WE TREAT HYPERPHOSPHATEMIA? Untreated hyperphosphatemia can lead to secondary hyperparathyroidism, renal bone disease, and is statistically associated with vascular calcification, increased morbidity, and mortality. 5 7 Consequently, phosphate control has become an important therapeutic target in CKD, primarily in the hope of reducing the risk of vascular calcification and cardiovascular mortality, although evidence that this is achievable is lacking. Indeed, Bushinsky 8 makes the point that there are no data demonstrating that a reduction of serum phosphorus will improve survival but also notes that a prudent clinician cannot dismiss the compelling epidemiologic evidence and will strive to lower serum phosphorus 906 Kidney International (2009) 75,

2 AJ Hutchison: Oral phosphate binders t r a n s l a t i o n a l n e p h r o l o g y Table 1 Ideal characteristics of an oral phosphate binder High affinity for binding phosphate low dose (pill burden) required Rapid phosphate binding regardless of ambient ph Low solubility Little to no systemic absorption Non-toxic and without Solid oral dose form Palatable (encourages compliance) Inexpensive Table 2 Comparison of oral phosphate binders in general use Phosphate binder Advantages Disadvantages Aluminum salts High efficacy regardless of ph Inexpensive Aluminum toxicity No definite safe dose Frequent monitoring needed intake 1400 mg/day Digestive juice phosphorus Phosphate binder 210 mg/day Formation 210 mg/day Bone Serum phosphorus (Pi) per 100 ml mml/l Resorption of P and Calcium carbonate Calcium acetate Aluminum free Moderately effective Moderate pill burden Inexpensive Aluminum free Efficacy somewhat ph dependent Fairly inexpensive Lower calcium load than carbonate Efficacy influenced by ph Unpalatable Hypercalcemia Possible ectopic calcification Large tablets need to be swallowed Hypercalcemia Possible ectopic calcification Absorption of Ca Urinary P Magnesium salts Moderate pill burden Calcium and aluminum free Moderate efficacy Moderate pill burden Not widely used Magnesium monitoring Excretion of P Stool 490 mg/day Figure 1 Effects of oral phosphate binders. Urinary Ca Urine 910 mg/day in dialysis patients. Consequently, hyperphosphatemia has now been added to the list of cardiovascular risk factors seen in CKD. 9 MANAGEMENT OF HYPERPHOSPHATEMIA IN CKD The three key elements in the management of elevated serum phosphate are dietary restriction, drug treatment using oral phosphate binders (see Figure 1), and adequate dialysis. Dietary phosphate restriction is impractical for many patients, and a general decline in home cooking skills often means that supermarkets are indirectly responsible for patients phosphate, sodium, and potassium intake. 10,11 In addition, it can be restricted only to a certain extent without risking protein malnutrition, particularly in elderly patients. 12 Conventional 4-h, thrice-weekly hemodialysis removes approximately 1000 mg of phosphate per session, but this is generally insufficient to maintain phosphate levels within the recommended targets, even if oral phosphate intake is significantly restricted. Peritoneal dialysis removes slightly more than this when averaged over a week, but is still insufficient. 13 Although short-hours daily and slow nocturnal hemodialysis are much more effective in reducing serum phosphate levels, logistic, cost, and patient acceptance issues limit the widespread usage of these modalities. 5 Thus, around Sevelamer Lanthanum carbonate Magnesium iron hydroxycarbonate Calcium and aluminum free No gastrointestinal tract absorption Moderate efficacy Reduces total and low-density lipoprotein cholesterol Calcium and aluminum free Chewed, not swallowed whole High efficacy regardless of ph Low pill burden Calcium and aluminum free Releases magnesium beneficial? (Little published data) Expensive Efficacy influenced by ph High pill burden Binds fat-soluble vitamins Expensive Minimal gastrointestinal absorption Releases magnesium effect unknown 90% of dialysis patients continue to need oral phosphate binders in an effort to control their phosphate levels. ORAL PHOSPHATE BINDERS All currently available oral phosphate binders have limitations of one sort or another (Table 2) and available data from RCTs do not show the superiority of any one binder over another. Nevertheless, there has been a progressive evolution of oral binders from aluminum, through calcium salts, and on to newer agents such as sevelamer and lanthanum carbonate. The expense of the newer agents is such that it Kidney International (2009) 75,

3 t r a n s l a t i o n a l n e p h r o l o g y AJ Hutchison: Oral phosphate binders is essential that the nephrology community organizes appropriate trials to show the benefits of phosphate reduction and the relative merits of oral binders versus alternative therapeutic strategies. ALUMINUM SALTS Aluminum-based phosphate binders came into general use in the 1970s. They are still used on a small scale as they are highly effective, but are associated with cognitive disturbances, osteomalacia, and anemia. 14,15 Aluminum successfully reduces serum phosphate levels through two mechanisms. First, aluminum hydroxide is able to form coordination compounds with phosphate ions, and thus trap and mask phosphate ions in the blood. Second, aluminum ions form aluminum phosphate precipitates in the gut, which are insoluble and cannot be absorbed. No safe dose of aluminum has been identified, and dialysis patients who take it even in modest doses have been reported to develop clinical evidence of toxicity Nonetheless, aluminum salts are still used as short-term salvage therapy to achieve acute control of high phosphate levels, and are also used in patients whose prognosis is felt to be so short, because of other comorbidities, that the advantages may outweigh the risks. Other oral phosphate binders, such as cerium oxide, 20 were examined in the 1980s as the toxicity of aluminum came to light, but the discovery that calcium carbonate was effective and inexpensive meant that very few were developed further. CALCIUM AND MAGNESIUM SALTS Calcium-based binders (acetate and carbonate) bind phosphate ionically and are effective 21 and inexpensive, but their administration results in hypercalcemia in up to 50% of patients, especially when co-administered with vitamin D analogs. 22 In addition, they can result in over-suppression of parathyroid hormone and the development of adynamic bone. 23 They have been associated statistically with both soft tissue and vascular calcification, 24 but remain in widespread use, primarily because of their combination of efficacy and low cost. Although now blamed by many for accelerating vascular calcification, it is worth remembering that vascular calcification was first seen in the 1960s when aluminum hydroxide was the only commonly available phosphate binder. 25 Calcium acetate is generally accepted to be more effective in binding intestinal phosphate, per mmol of administered elemental calcium, than calcium carbonate Compliance and tolerability of calcium acetate are possibly less good, and the studies showing a greater reduction in mean serum phosphate level, compared with the same dose of calcium carbonate, were relatively short-term but also examined cost-benefit and reported an advantage compared with sevelamer. 30 Other calcium-containing binders that are much less widely used include calcium alginate (25% elemental Ca) 31,32 and calcium lactate (12%). 33 Calcium ketoglutarate is a semisynthetic analog of the amino acid glutamic acid that exerts phosphate-binding properties, apparently without inducing hypercalcemia Reduction of dialysis fluid calcium concentration was shown to permit administration of increased doses of calcium carbonate resulting in better phosphate control without worsening hypercalcemia in peritoneal dialysis patients. 37 A number of similar studies have examined the serum effects of alteration of dialysate calcium concentration, but very few directly measure calcium balance, and there are no recent analyses in the CKD stage 3 or 4 population. In health, a balanced diet provides mmol of calcium per day, but varying amounts are absorbed by the intestines under the influence of vitamin D. Normal urinary calcium excretion varies from 2.5 to 7.5 mmol/day, with the balance appearing in the feces. 38 Total body calcium ranges from 1.0 to 1.5 kg (or about 1.5% of total body weight), of which 99% is stored in the bones. A 1.25 g tablet of calcium carbonate contains 12.5 mmol of elemental calcium, so that as CKD progresses toward dialysis and serum phosphate rises, the addition of four calcium carbonate tablets per day provides an additional 50 mmol of elemental calcium. In a study of dialysis patients with low 1,25-dihydroxyvitamin D3 levels, calcium absorption rate was subnormal in 18 of 19 subjects, with fractional absorption at 120 min ranging from as low as 3.2 up to 24% of the oral dose. 39 Presumably in the presence of an oral vitamin D analog, this percentage would increase significantly. Therefore, in an anuric dialysis patient prescribed oral vitamin D and with a daily calcium ingestion of 60 mmol, one would anticipate around 15 mmol absorption and no urinary losses. Hemodialysis against a dialysate calcium of 1.25 mmol might remove mmol per session, or 2 5 mmol/day when averaged over 1 week 40 giving a potential daily positive calcium balance of mmol ( mg). If skeletal metabolism is normal, much of the balance may be stored there, but in the presence of an adynamic skeleton this may be impossible. The arguments around the continued use of calciumbased binders were clearly and forcefully set out in 2006 by Friedman, 41 and Moe and Chertow. 42 Friedman argues that the evidence against calcium is inconclusive and does not outweigh its financial cost, whereas Moe and Chertow 42 argue that vascular calcification is a cell-mediated process accelerated by hyperphosphatemia and excess calcium load, and that in prospective, randomized studies, calcium-based phosphate binders lead to increased arterial calcification. Sadly, it is not possible at present to know definitively which opinion is correct, because the evidence on both sides is inconclusive, and firm evidence does not exist. Friedman 43 rightly calls for a head-to-head prospective trial of phosphate binders in which all other circumstances are held constant, overseen by a supervisory committee with no investigator commercial links to study drugs. Were there not such a large price differential between calcium and non-calcium-containing binders, such a trial would probably be unnecessary, and many clinicians would simply err on the side of caution, as 908 Kidney International (2009) 75,

4 AJ Hutchison: Oral phosphate binders t r a n s l a t i o n a l n e p h r o l o g y advised by Bushinsky 8 who comments that normalizing serum phosphorus in dialysis patients without adding calcium seems most prudent. However, from a financial viewpoint, this option is simply not available to the majority of patients being managed within cash-limited health-care systems. As a result, in many countries the debate cannot focus purely on clinical issues when incontrovertible evidence is lacking. Furthermore, the cost of such a trial will be large. Following the negative result of the Dialysis Clinical Outcomes Revisited 44 (DCOR) trial, it is unlikely that a pharmaceutical company would wish to fund it, and any result would be open to charges of bias. However, it would be well within the scope of a national funding body such as the NIH. Magnesium-containing phosphate binders can be used as an alternative to calcium-based agents but are generally less effective. They are associated with increased serum magnesium levels and diarrhea. 45,46 O Donovan et al. 47 used magnesium carbonate in 28 patients for 2 years as a substitute for aluminum hydroxide. Magnesium carbonate was administered in doses of mmol/day for the prestudy period and dialysate Mg concentration was changed from 0.85 mmol/l to low magnesium dialysate (0.25 mmol/l). Subsequently, a significant drop in predialysis aluminum levels was observed and serum phosphate was controlled and remained unchanged from previous levels. Magnesium levels remained between 1.01 and 1.33 mmol/l. All patients seemed to tolerate magnesium carbonate well. Despite a number of similar studies in the 1980s, magnesium salts are not widely used, but recently interest in them has revived 45 because of the possible beneficial effect of magnesium on vascular health. Magnesium is predominantly an intracellular cation with an important role in cellular physiology. Serum levels are often slightly elevated in dialysis patients. 48 and are influenced by the concentration of dialysate magnesium. 49,50 Retrospective studies suggest that magnesium may prevent vascular calcification in dialysis patients, although this remains controversial and has not been evaluated prospectively. 51,52 Magnesium may reduce arrhythmias postoperatively, and although it may theoretically reduce arrhythmic death in dialysis patients, this hypothesis has never been tested. Short-term or adjuvant use of magnesium carbonate appears safe and effective as a phosphate binder, but more studies are needed to evaluate the long-term effects on vascular calcification, bone histology, and mortality. Lower levels of serum magnesium have been recently associated with the presence of vascular calcification in hemodialysis patients, 53 and another recent study has shown that oral magnesium supplementation improves carotid intima media thickness in hemodialysis patients. 54 In the search for other alternatives to calcium-containing binders, a variety of unusual compounds has been examined including zirconyl chloride octahydrate. 55 The same author was the first to propose a salt of lanthanum as another possible phosphate binder. 56 SEVELAMER HYDROCHLORIDE AND CARBONATE Sevelamer hydrochloride was the first synthetic non-aluminum and calcium-free phosphate binder to become commercially available. It was originally developed to lower plasma lipids and also has this beneficial side effect in CKD patients. 57 Sevelamer is an aluminum and calcium-free non-absorbed poly (allylamine hydrochloride) polymer. It contains multiple amines separated by one carbon from the polymer backbone. These amines become partially protonated in the intestine and interact with phosphate ions through ionic and hydrogen bonding. In several open-label studies, sevelamer appears as effective as calcium-based binders in lowering phosphate, but without the tendency to promote hypercalcemia. 58 Furthermore, there is some evidence that sevelamer hydrochloride can attenuate coronary and aortic calcification compared with calcium-based phosphate binders. 59 Despite these advantages, gastrointestinal disturbances, metabolic acidosis, and cost are limiting factors affecting the wider use of sevelamer hydrochloride. 60 Unfortunately, the large pill burden required to achieve target phosphate levels can adversely affect patient adherence. A large prospective randomized study of sevelamer versus calcium binders was undertaken in an effort to show reduced mortality (the DCOR study), but unfortunately the 2-year trial produced a negative result, 44 and it remains unclear whether this represents methodological problems in the design and execution, or a genuine result. The results (Table 3) were originally presented at the 2005 ASN Renal week as a non-significant 9% reduction in all-cause mortality with sevelamer relative to the calcium-binder group (P ¼ 0.30). Whether a nonsignificant change can be considered as a reduction is doubtful. However, a subsequent post hoc analysis of subgroups suggested a survival advantage for patients aged over 65 years, but the statistical and clinical validity of this finding remains controversial. 61 More recently, St Peter et al. 62 conducted a secondary analysis and found that treatment with sevelamer versus calciumbased binders did not affect overall mortality (primary outcome), cause-specific mortality, morbidity, or first or cause-specific hospitalization (secondary outcomes), but there was evidence for a small but beneficial effect on the secondary outcomes of multiple all-cause hospitalizations (1.7 versus 1.9 admissions/patient-year; P ¼ 0.02 adjusted) and hospital days (12.3 versus 13.9 days/patient-year; P ¼ 0.03 adjusted). The use of sevelamer does not completely abolish hypercalcemia, but different studies have produced widely variable results, presumably reflecting differences in diet, vitamin D dosage, and dialysate calcium concentrations. Qunibi et al. 30 report no hypercalcemia with sevelamer in the CARE study, compared with 2 9% with calcium acetate. However, the sevelamer group experienced a 7 24% incidence of hypocalcemia compared with 2 13% incidence in the calcium acetate group. In marked contrast, Asmus et al. 63 reported 26 and 6% of patients on sevelamer experiencing calcium levels greater than 10.4 and 11.2 mg per 100 ml, Kidney International (2009) 75,

5 t r a n s l a t i o n a l n e p h r o l o g y AJ Hutchison: Oral phosphate binders Table 3 Dialysis Clinical Outcomes Revisited trial: primary end point (all-cause mortality) 44 End point Sevelamer Calcium binders Relative risk (95%) Deaths, n (%) 265 (26) 274 (27) 0.91 ( ) Mortality incidence rate (per 100 patient-years) Table 4 Reported incidence of hyper and hypocalcemia in studies of sevelamer hydrochloride and lanthanum carbonate Hypercalcemic patients (%) Hypocalcemic patients (%) Sevelamer Asmus et al (410.4 mg per 100 ml) NR 6(411.2 mg per 100 ml) Qunibi et al Bleyer et al NR Lanthanum Hutchison et al Finn Hutchison et al Note: Precise definitions of hyper/hypocalcemia vary or are not specified in these publications, which therefore may not be directly comparable. NR denotes data not reported in the manuscript. respectively, compared with 54 and 27% in the calcium carbonate group (Table 4). Many studies undertaken with sevelamer have been designed to assess its superiority to older calcium-based phosphate binders. 67,68 The RIND study went beyond biochemical targets to look prospectively at effects on coronary artery calcification but was unable to show effects on mortality. At start of dialysis, around one-third of patients had little evidence of calcification and did not develop any, after 12- to 18-month follow-up, regardless of the type of oral phosphate binder prescribed. However, those patients with calcification at baseline appeared to progress more rapidly if using calcium-based binders rather than sevelamer. Unfortunately, this type of study raises as many questions as it answers. A more recent formulation of sevelamer as a carbonate has recently been approved for use, and appears to solve the problem of mild acidosis associated with sevelamer hydrochloride. 69 LANTHANUM CARBONATE Lanthanum carbonate became available in the United States in 2005 and in the EU in Preclinical animal studies suggested that lanthanum might be similar to aluminum in phosphate binding capacity but with a more favorable safety profile. As a trivalent cation, it binds phosphate ionically, and similar to sevelamer it is a non-aluminum-, non-calcium-based binder, but with low systemic absorption. The small fraction of the oral dose that is absorbed (o0.0013%) undergoes binding to proteins in the plasma and also biliary excretion after transiting through the liver within lysosomes In a large prospective randomized European multicentre open-label comparator trial, the efficacy of lanthanum carbonate was compared with calcium carbonate. 66 In total, around 800 patients were randomized (533 to lanthanum and 267 to calcium carbonate). The primary end point was reduction of serum phosphate levels to p1.8 mmol/l. After 9 weeks of treatment, both groups had serum phosphate levels of around 1.69 mmol/l. The proportion of patients achieving controlled phosphate levels of o1.8 mmol/l was similar in both treated groups (lanthanum 65.8%, calcium 63.9%) at the end of the maintenance phase. Perhaps most importantly from a clinical perspective, there was a significantly lower incidence of hypercalcemia in the lanthanum group (0.4%) than in the calcium-treated group (20.2%), as one would expect with a non-calcium-based binder. The relative potency of lanthanum carbonate as a binder translates into a reduced pill burden that may aid patient adherence to therapy. 73 In the same way that the use of sevelamer does not abolish hypercalcemia, the use of lanthanum not reduce the risk to zero either. Studies document hypercalcemia being reported as an adverse event in 0.4, 0.6, and 4.3% of subjects taking lanthanum carbonate monotherapy; however, the incidence of single transient episodes not regarded by the clinician as adverse is much higher, at up to 37% in one long-term observational study. 64 Similarly, hypocalcemia reported as an adverse event was seen in 3.1 and 7.0% of patients in longterm studies (Table 4). Concerns have been expressed about the long-term safety of lanthanum carbonate in dialysis patients, with regard to bone and liver toxicity. 74 However, reports of its use over 1 year, 3 years, and most recently 6 years appear to have shown a satisfactory long-term safety profile, with no evidence of harmful. 64,75,76 More recently, a speculative comparison has been made between lanthanum and gadolinium with the suggestion that it might have the potential to cause nephrogenic fibrosing dermopathy. 77 However, the serum levels achieved after a dose of intravenous gadolinium are of the order of 400,000 times those seen after long-term oral treatment with lanthanum, which in addition is highly protein bound. 78 Furthermore, free gadolinium is known to be toxic to tissues and has to be sequestered to make it safe for clinical use by binding to organic chelates to form stable complexes. 79 In contrast, there is no evidence of similar toxicity with lanthanum. De Broe concluded that these two trivalent cations differ substantially in their metabolism, pharmacokinetics, and most importantly their clinical use and toxicity. MAGNESIUM IRON HYDROXYCARBONATE Magnesium iron hydroxycarbonate is another new oral phosphate binder currently undergoing clinical trials, with promising results presented in abstract form only, so far. 80 Its use is associated with increased serum magnesium levels, the effect of which on bone function is currently unknown. 910 Kidney International (2009) 75,

6 AJ Hutchison: Oral phosphate binders t r a n s l a t i o n a l n e p h r o l o g y However, it is clear that hypomagnesemia is associated with reduced bone mineral density in both rats and humans, and hypermagnesemia has been associated with reduced vascular calcification, 51 so this may be beneficial. On the other hand, hypermagnesemia has also been associated with adynamic bone 85 and there are rare reports of it causing quadriparesis and even death in extreme cases. 86,87 GASTROINTESTINAL PHOSPHATE ABSORPTION BLOCKADE Over 10 years ago, Katai et al. 88 showed that nicotinamide could inhibit sodium-dependent phosphate co-transport activity in the rat small intestine, but it was not until 2004 that another Japanese group used oral nicotinamide in a group of 65 hyperphosphatemic dialysis patients. 89 These patients discontinued their existing oral phosphate binder therapy allowing serum levels to rise, and then commenced oral nicotinamide at a mean dose of 1080 mg daily. Over a 12-week follow-up period, serum phosphate levels returned to their pre-study level of around 5.4 mg per 100 ml, with no effect on serum calcium and a beneficial rise in serum highdensity lipoprotein plus a fall in low-density lipoprotein. The authors proposed that nicotinamide could be a useful alternative method of controlling serum phosphate, but it seems possible that it could also be used as an additive treatment. Similar findings were described by Eto et al. 90 in rats with renal failure. are likely to limit the dosage of nicotinamide, but the blockade or inhibition of the intestinal transport mechanism by alternative molecules is an attractive possibility. Interestingly, fructose has very recently been described as having this effect. 91 PATIENT EDUCATION TO ASSIST CONTROL OF SERUM PHOSPHATE The quantity of information that dialysis patients need to understand, to participate in their own management is substantial. No other current medical intervention requires such detailed knowledge of fluid balance, dietary control, medication timing, and dosage, plus the dialysis process itself for a home dialyzer. Few medical staff or nurses have additional qualifications in teaching, yet there seems little doubt that time spent with the patient is beneficial and several studies have shown that patient education programs are associated with an improvement in serum phosphate control, although repeated reinforcement is required. 95 Most adults are aware of the importance of controlling blood pressure, cholesterol, and body mass index, even if they do not have any illness. However, they are very unlikely to have come across any public health messages concerning phosphate, and therefore it is incumbent on the CKD team to provide appropriate education. Where this has been trialed, the results have been encouraging, particularly where easily understood visual aids have been used. 96 WHERE DO WE GO FROM HERE? Figures often beguile me, Mark Twain wrote, particularly when I have the arranging of them myself. 97 Sadly, it seems that the nephrology community is currently beguiled in a similar manner. Observational studies have produced numerous statistical associations, which have in turn given rise to a multitude of opinion-based guidelines. Although the authors of the K/DOQI guidelines clearly stated that Since the majority of the recommendations made in this set of guidelines are based on opinion, it is imperative that evaluation of their clinical outcomes be made a component of their implementation. 98 We have collectively failed to do so. Consequently, although we know that high serum phosphate levels are associated with increased risk of death, there is no incontrovertible evidence that reducing serum phosphate levels will prolong life. 8 The likelihood of 5-year survival on dialysis, for a 60-yearold patient in Europe and the United States, is currently around 46 50%, which is only marginally better than that of a similar aged woman with ovarian carcinoma (45%). 99 Furthermore, an ovarian cancer survivor at 5 years is likely to have been cured, whereas the mortality associated with dialysis continues relentlessly. Nevertheless, nephrologists are content to spend ever increasing amounts of money on expensive pharmaceutical agents with little evidence that they will improve survival or quality of life. The reasons for this parlous state of affairs are numerous and complex. First, licensing authorities such as the US Food and Drug Administration and the European Medicines Agency generally do not require outcome studies for approval. They are focused on safety and efficacy. By publishing guidelines with biochemical targets, nephrology has provided the standard by which to judge efficacy yet no cancer drug would be assessed in this manner. Second, RCTs are difficult to conduct in nephrology because they require multicenter cooperation and long duration of follow-up, with significant associated expense. Such studies would need to be organized with the cooperation and funding of large pharmaceutical companies. However, it is not in their interests to do this so long as we are content to keep prescribing new and ever more expensive agents, in a vain effort to achieve self-imposed (albeit pharma sponsored 100 ) biochemical targets. 101 To make matters worse, our guidelines limit or prohibit the use of older and cheaper agents such as calcium carbonate and acetate largely on the basis of observation and opinion. Third, we seem to repeatedly ask the wrong whether one oral phosphate binder is better than another is only relevant when we can show that lowering serum phosphate, and to what extent, will improve clinical outcomes. 102,103 It seems unlikely that an ethics review board would sanction a trial of a phosphate binder versus placebo with an unlimited upper level of phosphate, but it would be reasonable to test the theory that controlling serum phosphate to a range of mg/dl per 100 ml might be advantageous compared with mg/dl. Which specific binder one would use for such a study is a difficult question. Ideally, one would want four groups calcium, and high phosphate, non-calcium, and high phosphate but this Kidney International (2009) 75,

7 t r a n s l a t i o n a l n e p h r o l o g y AJ Hutchison: Oral phosphate binders would add considerably to the cost and complexity of the trial and would probably preclude sponsorship from pharmaceutical companies at least. CONCLUSION Hyperphosphatemia is prevalent in the dialysis population and is considered by many to be an independent risk factor associated with cardiovascular morbidity and mortality. Its control remains a challenging issue for clinical nephrologists because none of the traditional therapeutic approaches appear entirely satisfactory. Dietary restrictions are difficult to follow and standard hemodialysis is inadequate for removal of phosphate, so that the vast majority of dialysis patients require oral phosphate binders. Until recently, none of the available agents fulfilled the criteria of an ideal phosphate binder. Aluminum- and calcium-based binders have numerous drawbacks, but are inexpensive. The introduction of sevelamer hydrochloride, and subsequently of lanthanum carbonate, represent significant developments in phosphate management. Both are nonaluminum, calcium-free agents, but are expensive. Sevelamer achieves effective phosphate lowering and may attenuate progression of vascular calcification in hemodialysis patients. Lanthanum carbonate represents another step on the way to complete phosphate control. Evidence suggests that it is an effective, well tolerated, and safe phosphate binder. Patient education programs have been shown to be an effective adjunct to other methods of phosphate control. Sadly, randomized prospective outcome studies of the benefits of reducing serum phosphate have yet to be undertaken, and the achievement of targets set by opinionbased guidelines seem to have become accepted outcomes in themselves. It is to be hoped that the eagerly awaited KDIGO CKD-MD guidelines will acknowledge the lack of good quality data, and stimulate high quality RCT-based research, rather than a plethora of publications that seek only to measure the achievement of biochemical targets. If so, perhaps we can really begin to understand first the role of serum phosphate, and second, that of oral phosphate binders, in the management of patients with CKD. DISCLOSURE Dr Hutchison has received research grants from and is a consultant for Shire Pharmaceuticals. REFERENCES 1. Burke SK. Phosphate is a uremic toxin. J Ren Nutr 2008; 18: Foley RN, Parfrey PS, Harnett JD et al. Hypocalcemia, morbidity, and mortality in end-stage renal disease. Am J Nephrol 1996; 16: Lamb EJ, Hodsman A, van SD et al. Serum calcium, phosphate, parathyroid hormone, albumin, aluminium and cholesterol achievement on replacement therapy (chapter 9). Nephrol Dial Transplant 2007; 22(Suppl 7): vii105 vii Strippoli GF, Craig JC, Schena FP. 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