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Based on the following article: Sprague SP. Current Medical Research and Opinion 2007;23(12):3167-75

Reported by:

David C. Mendelssohn, MD, FRCPC

Chief/Physician Director, Department of Nephrology, Humber River Regional Hospital, Weston, Ontario

Associate Professor of Medicine, University of Toronto, Toronto, Ontario

Disorders of mineral metabolism begin earlier in chronic kidney disease (CKD) than previously suspected, especially with low levels of 1,25-dihydroxyvitamin D and high parathyroid hormone (PTH) (Levin et al. Kidney Int 2007;71:31-8). Serum phosphate and calcium are altered later in the course of CKD (Craver et al. Nephrol Dial Transplant 2007;22(4):1171-6), such that by CKD stage 4, many patients have elevated levels of serum phosphorus. These mineral abnormalities may interact in such a way as to contribute to the excess morbidity and mortality seen in hemodialysis patients and even among those who have yet to reach end-stage renal failure.

Traditional methods of dialysis are not adequate to remove enough phosphorus from the blood to achieve Kidney Disease Outcomes Quality Initiative (K/DOQI) targets for serum phosphorus. Nocturnal hemodialysis as offered to some patients in our own hospital is far more effective at removing phosphorus—so much so that the majority of these patients can come off phosphate binders altogether. Unfortunately, for largely budgetary reasons, nocturnal hemodialysis is available to a very small proportion of patients with end-stage renal disease. Thus, the lion’s share of the management of hyperphosphatemia falls to restrictive diets and the various phosphate binders currently available to us.

In a review of phosphate binders now commonly used here and elsewhere, Dr. Stuart Sprague, Northwestern University Feinberg School of Medicine, Evanston, Illinois, discusses the advantages and disadvantages of calcium acetate, calcium carbonate (the latter by far and away the most frequently prescribed phosphate binder here in Canada), sevelamer hydrochloride (HCl) and lanthanum carbonate (Curr Med Res Opin 2007;23:3167-75). (Aluminum-based binders are still used to a small extent in Canada but while effective, they have been associated with heavy-metal toxicity including osteomalacia, encephalopathy and refractory anemia and they are no longer recommended.)

It should be stated first and foremost that no study has ever demonstrated any one phosphate binder reduces serum phosphorus any more effectively than the others. How phosphate binders do differ is in their mechanism of action to some extent; the doses needed to achieve K/DOQI targets; the potential for adverse consequences; and the number of pills patients need to take to keep phosphorus under control. As Dr. Sprague points out, all phosphate binders bind to dietary phosphate in the gastrointestinal (GI) tract, where they form insoluble complexes. The calcium salts specifically bind phosphate in the digestive tract by dissociating into calcium and their respective anions, at which point, elemental calcium can bind to dietary phosphate where it forms an insoluble calcium phosphate precipitate. This prevents the absorption of calcium and facilitates fecal elimination.

Yet calcium salts may lead to positive calcium balance, especially if patients are taking non-selective vitamin D compounds, which promote GI absorption of calcium. As the first available non-calcium-based binder, sevelamer HCl releases chloride ions in exchange for phosphate ions, although this exchange is largely pH-dependent and requires a higher pH environment as is found in the small intestine. Sevelamer can also bind with a number of different anions, including the bile salts, and it is through this action that this particular phosphate binder is thought to reduce cholesterol as well as LDL-C. Although sevelamer’s non-selectivity for phosphate is a desirable property, bile acids may be bound at the expense of phosphate, thereby compromising the agent’s potency.

In contrast, lanthanum carbonate dissociates in the acid environment of the upper GI tract, where its trivalent cations bind with dietary phosphate to form insoluble, non-absorbable lanthanum phosphate complexes which in turn are fecally eliminated. Binding and removal of lanthanum carbonate also operates independently of pH, a property that likely contributes to its potency as a phosphate binder relative to that of both calcium-based binders as well as sevelamer.

Calcium Debate Continues

The debate over whether calcium-based binders contribute to excess cardiovascular (CV) morbidity and mortality in CKD patients continues, but evidence is accumulating to support this hypothesis. One of the most widely cited studies compared the effect of a calcium binder vs. that of sevelamer on progression of coronary and aortic calcification.

As reported by Chertow et al. (Kidney Int 2002; 62:245-52), the Treat-to-Goal study randomized prevalent hemodialysis patients to either a calcium-based binder or sevelamer and followed them for a total of 52 weeks. During this interval, mean serum phosphorus levels were virtually identical across all patient groups and an equivalent per cent of patients were at K/DOQI targets for CKD stage 5. However, at week 52, the 25% mean change in the coronary artery calcification score (CACS) amongst the calcium-based binder recipients was significantly greater than the 6% change seen among sevelamer patients.

Similarly, the mean change in the aortic calcification score was also significantly greater in patients receiving a calcium binder than in those taking sevelamer. Notably, LDL-C levels were significantly lower in the sevelamer arm than among those taking a calcium-containing binder, which might explain at least some of the difference seen in the calcification scores between the two groups.

The Treat-to-Goal study is not the only one to suggest that a surfeit of calcium is detrimental to the vasculature. The Renagel in New Dialysis (RIND) study by Block et al. (Kidney Int 2005;68:1815-24) randomized incident hemodialysis patients to either a calcium-based binder or sevelamer. Over the 18-month trial, average phosphorus control was again virtually identical between the two groups. Again, however, there was a marked difference in calcification scores between those on a calcium-based binder vs. those on sevelamer, median CACS scores being significantly greater among patients taking a calcium-based binder. Yet patients who had no evidence of coronary artery calcification upon initiation of dialysis had little evidence of coronary calcification during follow-up, suggesting that there are a minority of dialysis patients who have little propensity towards vascular calcification, regardless of the binder used.

More recently, in the RIND extension study, Block et al. also reported that the median absolute increase in the CACS was 11-fold greater in calcium-treated patients with a baseline CACS>30 compared with their sevelamer counterparts (Kidney Int 2007;7(15):435-41). Baseline CACS was also a strong predictor of mortality at 18 months’ follow-up, validating the use of this measure as a surrogate marker for mortality risk. Importantly, the assignment of phosphate binder was significant, with the use of a calcium-containing binder being associated with a 2.2-fold increase in mortality compared with sevelamer.

A recent large mortality trial in prevalent hemodialysis patients compared calcium-based binders with sevelamer. The DCOR(Dialysis Clinical Outcomes Revisited) study showed a trend towards improved survival with sevelamer, but the difference did not reach statistical significance. This study was flawed in that it was designed to detect too large a difference in mortality rates, and so was ultimately underpowered.

In another study by Russo et al. (Kidney Int 2007;72(10):1255-61), investigators followed the progression of coronary artery calcification in normophosphatemic predialysis patients not on phosphate binder therapy but who were randomized to a low-phosphorus diet plus either calcium carbonate or sevelamer. Patients were then followed for approximately two years. At study end point, the total calcium score was significantly greater than the initial score in control subjects on the diet alone and in calcium carbonate subjects, but it was not significantly different from the initial total calcium score in those receiving sevelamer.

These studies suggest at the very least that a non-calcium-based binder should be preferentially considered in patients with CV calcification and that phosphate-binder therapy may well be needed in earlier-stage CKD than is currently considered.

Compliance Issues

Given that phosphate binders are equally effective at controlling hyperphosphatemia, why is it that our success rate at achieving K/DOQI targets for serum phosphorus is still only around 60%, according to the largest survey of hemodialysis patients carried out in Canada, as reported at least year’s American Society of Nephrology meeting? The answer likely comes down to compliance with phosphate-restricted diets and with phosphate binders. According to Curtin et al. (ANNA J 1999;26:307-16), over 70% of hemodialysis patients were assessed as being repeatedly non-compliant with phosphate binder therapy, although only 8% of patients considered themselves to be so.

Phosphate-binder therapy also adds to the complexity of treatment regimens. Guidelines for calcium and phosphorus control are difficult to achieve without full compliance to a binder regimen. In addition, guidelines specify that we limit our use of a calcium-containing binder to 1500 mg/day of elemental calcium, otherwise we risk inducing positive calcium balance.

This K/DOQI recommendation is often ignored in Canada, however, for in order to adequately reduce serum phosphorus, we often need to go to 4 g/day or more of calcium binder. With a standard 500-mg dose of calcium carbonate, patients would typically need to take eight tablets a day and if we use calcium acetate, the pill burden would be even higher at up to 12 capsules/day. The recommended starting dose of sevelamer is between 800 and 1600 mg/day, to be given as one to two 800-mg capsules or two to four 400-mg capsules with each meal, depending on serum phosphorus levels.

But several clinical trials indicate that the mean total daily maintenance dose for sevelamer ranges from 4.9 g/day to 6.9 g/day, or six to nine 800-mg tablets a day. A study by Qunibi et al. (Kidney Int 2004;65:1914-26) reported a mean of 10.7 pills/day for those taking calcium acetate and 17.2 pills for those on sevelamer. It is evident that regardless of which phosphate binder is used, they all represent a very large pill burden for patients. Moreover, non-compliance to binder requirements has no immediate impact on a patient’s well-being, as hyperphosphatemia is largely silent in its less severe stages.

As a non-calcium-containing phosphate binder, it is believed that lanthanum carbonate will not contribute to vascular calcification. It is also a very potent phosphate binder, as it has both a high affinity for phosphate and is unaffected by variations in pH or by the presence of bile acids, unlike calcium-containing binders and sevelamer. The recommended starting dose for lanthanum carbonate is 750 to 1500 mg/day to be divided and taken three times daily with each meal. At a total daily maintenance dose of between 1.5 and 3 g, most patients can take one tablet per meal, or three tablets a day to achieve K/DOQI phosphate targets.

This substantially reduced pill burden has reportedly led to significantly greater patient and physician satisfaction with their phosphate binder therapy. As reported by Mehrotra et al. (J Am Soc Nephrol 2006; 17:356A), patients were switched from either sevelamer or a calcium-based binder at baseline to a dose of lanthanum carbonate 750 mg or the 1000-mg tablet. After four weeks of treatment, 82% of patients and 85% of physicians expressed a higher level of overall satisfaction compared with previous phosphate-binder therapy, and satisfaction remained higher among both cohorts after two months of treatment. Patients also overwhelmingly preferred lanthanum carbonate (79%) to their previous binder therapy (15%), as did physicians.

Whether a higher level of overall satisfaction with lanthanum carbonate than other phosphate binders translates into improved compliance needs further study, but reducing the pill burden certainly simplifies the regimen. Patients will also likely find a one-pill-per-meal schedule more tolerable, although lanthanum carbonate needs to be chewed, not swallowed. This would exclude its use among patients unable to chew.

Reassessing Safety

Data for lanthanum carbonate are limited to safety and efficacy in humans. Those data may be reassuring so far, but further studies are clearly in order to determine whether treatment has a salutary effect on vascular calcification as well as on hard clinical end points. As noted by Sprague, no adverse effects have yet been observed with five to six years of continuous therapy on either liver function, bone or the central nervous system. Although the number of patients who have remained on longer-term therapy are small, they are likely to continue to grow with increased use of lanthanum carbonate and increased numbers may help alleviate any lingering concerns about long-term safety of the drug.

There have been some concerns expressed about lanthanum because, like aluminum, it is a trivalent cation heavy metal element. According to Behets et al. (Curr Opin Nephrol Hypertens 2004;13:403-9), for example, lanthanum carbonate is only minimally absorbed from the gut at a rate of 0.00089% in man vs. 0.01% to 0.1% for aluminum-containing phosphate binders. Elimination of lanthanum is minimally dependent on renal function, but rather on the liver, an important consideration in patients with chronic renal insufficiency (Persy et al. Semin in Dial 2006;19:195-9).

There is a reason why many of us prescribe over-the-counter calcium-based antacids for phosphate control, which can be attributed to easy access and affordability. In contrast, non-calcium-containing phosphate binders cost about $4000 per year. Presently in Ontario, the use of sevelamer is restricted to only a small proportion of patients who meet the government-imposed access criteria. If patients or physicians want it, they usually must pay for it themselves unless they have private insurance. Also in Ontario, lanthanum carbonate does not even have restricted access criteria and patients must cover the cost of treatment themselves, unless they have private insurance that covers phosphate-binder therapy. Improving access to non-calcium-containing phosphate binders has a rational scientific basis and seems likely to improve patient outcomes. But for the time being, the prescription is often made according to government policy based on cost and not necessarily potential benefit, an unfortunate reality across many therapeutic areas today.

Summary

In my view, control of hyperphosphatemia in dialysis patients—and maybe even predialysis patients with normal serum phosphorus levels but evidence of coronary calcification—is a key emerging issue in the management of CKD patients. So, too, is the issue of non-compliance. Both the calcium-based binders and sevelamer are effective but they are associated with a high pill burden, leading to patient fatigue with complex regimens and eventual non-compliance. If more data and longer-term follow-up confirm initial findings of safety and efficacy with lanthanum carbonate, then it will become an important therapeutic option in the management of high phosphorus levels and has the potential to improve phosphate control for CKD patients by reducing pill burden and fostering compliance.