Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

National Kidney Foundation Spring 2007 Clinical Meeting

Orlando, Florida / April 10-14, 2007

Among the multiple risk factors that contribute to the challenge of managing chronic kidney disease (CKD) are elevated levels of serum phosphorus (Figure 1). As discussed by Stuart Sprague, DO, Professor of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, investigators have found that risks for all-cause death, death from coronary artery disease (CAD) and fatal/non-fatal myocardial infarction (MI) are all higher as serum phosphorus levels increase, even in individuals with normal renal function (Tonelli et al. Circulation 2005;112:2627-33).

Other abnormalities in mineral metabolism, including elevated serum calcium and both very low and elevated levels of parathyroid hormone (PTH), are also associated with an increased likelihood of death in CKD patients.

Calcification in Dialysis Patients

Part of the reason why cardiovascular (CV) morbidity and mortality rates are so high in the CKD population is related to arterial calcification: the greater the degree of arterial calcification, the greater the risk of death.

In a study of end-stage renal failure patients, for example, there were almost no deaths over a follow-up interval of some 80 months in patients who had no calcified arteries at baseline compared with an approximately 80% mortality rate for those with four calcified arteries (Blacher et al. Hypertension 2001;38:938-42).

As Dr. Sprague indicated, aortic pulse wave velocity is a measure of arterial stiffness and arterial calcification, and increases in pulse wave velocity are an indication that arterial calcification is present, as are elevations in pulse pressure.

Figure 1. Serum Phosphorus: Mortality Rates

“As such, pulse pressure is an easy measure by which to assess arterial stiffness in our patients,” Dr. Sprague suggested.

Certainly, a high calcium intake increases the likelihood that patients will have an elevated calcification score; this in turn, is directly related to an increased mortality risk (Figure 2). Furthermore, as observed by Dr. Dennis Andress, Clinical Professor of Medicine, University of Washington School of Medicine, Seattle, relatively high calcification scores have been observed with what most physicians would consider “acceptable” levels of calcium intake at between 1.8 and 2.1 grams of elemental calcium per day (Guérin et al. Nephrol Dial Transplant 2000;15:1014-21, Hsu et al. Am J Kidney Dis1997;29:641-9), suggesting that targets for elemental calcium should probably be lower.

Other abnormalities in mineral metabolism also contribute to CV disease risk, as Dr. Andress observed. For example, Teng et al. (J Am Soc Nephrol 2005;16:1115-25) showed that mortality risk increases by approximately 30% in dialysis patients not receiving intravenous vitamin D if their PTH levels are in the range of 400 to 500 pg/mL compared with normal PTH levels.

Of increasing concern in dialysis patients is the risk of adynamic bone disease. As speakers here explained, adynamic bone disease is caused by increased serum calcium levels and over-suppression of PTH. “The worry about adynamic bone disease is calcium-loading,” Dr. Andress told delegates, “and we need to identify patients [with adynamic bone disease] so we can take them off calcium-based binders.” Contrary to historical belief, vitamin D therapy is actually beneficial for patients with adynamic bone disease, Dr. Andress added, by stimulating bone formation and inhibiting bone resorption.

In one study of stage III and IV CKD patients who received an active vitamin D analogue, PTH levels were suppressed by about 30% and bone densities actually increased compared to placebo, noted Dr. Andress (Rix et al. Nephrol Dial Transplant 2004;19:870-6). The same observation has been made in dialysis patients given calcitriol (Ruedin et al. Kidney Int 1994;45:245-52) and a survival advantage has been shown for dialysis patients treated with intravenous vitamin D sterol therapy (Teng et al.).

However, there does appear to be differences in effects on vascular calcification between the vitamin D analogues, as Dr. Andress demonstrated, as paricalcitol is apparently associated with little or no excess vascular calcification compared with both calcitriol and doxercalciferol (Slatopolsky et al. ASN 2006, Abstract SA-DS527).

Figure
d Calcification Score

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Non-calcium-Based Phosphate Binders

As discussed by Dr. William Finn, Professor of Medicine, University of North Carolina School of Medicine, Chapel Hill, the first non-calcium-based phosphate binder contained aluminum, which proved to be potent and inexpensive. But once absorbed, aluminum binders required functioning kidneys to eliminate and as a result, levels built up in dialysis patients, leading to an increased risk of neurological abnormalities and fracturing osteomalacia. Calcium-based phosphate binders had a better overall safety profile but limitations to their use include an increased risk of hypercalcemia and associated CV complications as well as renal osteodystrophy.

“There is also a high pill burden, requiring patients to take three to four tablets per meal and elemental calcium intake may exceed the Kidney Disease Outcomes Quality Initiative [K/DOQI] guidelines’ recommended maximum,” Dr. Finn added. Excess ingestion of alkali and calcium is also associated with the milk-alkali syndrome, which can lead to renal insufficiency, soft tissue calcification and nephrocalcinosis.

The first calcium- and aluminum-free phosphate binder was sevelamer and it was subsequently shown to cause significantly less coronary artery calcification than calcium binders (Braun et al. Clin Nephrol 2004;62:104-15). Block et al. also found that it enhanced survival compared with calcium binders (Kidney Int 2007;71:438-41). However, it does not bind phosphate well in lower levels of intestinal pH; it may bind to fat-soluble vitamins; and it does carry a risk of inducing metabolic acidosis. There is also a high pill burden, as Dr. Finn indicated, at an average of nine 800-mg tablets a day, based on phase III trial data.

The more recent introduction of lanthanum carbonate in both Europe and the US appears to avoid many of the limitations of sevelamer, especially its high pill burden. Clinical trials have clearly demonstrated that it decreases serum phosphorus and the calcium/phosphorus product to K/DOQI recommended targets (Finn W. World Congress of Nephrology 2003 Abstracts). It is also capable of binding phosphate at any level of intestinal pH so it is highly selective for phosphate binding, Dr. Finn noted. Unlike aluminum-based binders which require normal kidney function for excretion, what little of lanthanum carbonate is absorbed is excreted through the liver and no effect from this agent has yet been seen on liver function tests with continued treatment over six years.

Again unlike aluminum-based binders, lanthanum carbonate does not cross the blood-brain barrier and there is no sign that it affects cognitive function, based on results from a series of cognitive function tests. Nor does it have any deleterious effects on bone. In a poster presentation under lead author Dr. Hartmut Malluche, Professor and Chief of Nephrology, University of Kentucky A. B. Chandler Medical Center, Lexington, the effect of lanthanum carbonate on the evolution of abnormalities of bone turnover, bone balance and mineralization in stage V CKD patients was compared to standard calcium binder therapy.

Lanthanum carbonate was initiated at a dose of 750 to 1500 mg/day, and titrated to achieve a serum phosphorus of 5.5 mg/dL (1.8 mmol/L) or less. Paired baseline and one-year follow-up bone biopsies were available for 33 patients in the calcium binder group and 32 patients in the lanthanum carbonate group, while two-year follow-up biopsies were available for 24 patients in the standard therapy group and 32 patients in the non-calcium binder group. As investigators reported, both groups achieved similar levels of serum phosphorus control at one and two years.

No mineralization abnormalities have been reported in other longer-term studies of lanthanum carbonate where patients have been maintained on therapy for at least 4.5 years. In fact, in one study comparing lanthanum carbonate to a calcium binder, 12-month bone biopsies showed that the incidence of adynamic bone disease, essentially the same at baseline in both groups at approximately 20%, was lower with lanthanum carbonate at 9% after one year vs. 30% for calcium controls (D’Haese et al. Kidney Int Suppl 2003;63:S73-S78).

Perhaps most importantly, lanthanum carbonate at a dose of 1 g per meal is associated with a markedly reduced pill burden compared with other phosphate binders. In a poster presentation under lead author Dr. Nirupama Vemuri, South Florida Nephrology Group, Coral Springs, investigators converted 2763 patients from either a calcium or non-calcium-based phosphate binder to lanthanum carbonate and followed them for 12 weeks. In an intent-to-treat population of 2520 patients, 1751 of whom completed the study, investigators found patients on prior sevelamer therapy had a mean decrease of 3.4 tablets/day, while those on prior calcium binders had a mean decrease of 2.2 tablets.

Overall patient and physician satisfaction with lanthanum carbonate therapy was also higher than at baseline, where 73% of patients reported they preferred it to their previous phosphate binder, as did 83% of
.

Figure 3. Overall Patient/Physician Satisfaction with Therapy

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“Effective lanthanum carbonate doses for most patients were 3 g/day or less, which can be provided by a single tablet of lanthanum carbonate with each meal, simplifying treatment,” investigators concluded.

Low Pill Burden

Results from another analysis of the safety and efficacy of high-dose lanthanum carbonate confirm that it is both safe and effective at a low pill burden. As presented by Dr. Rajnish Mehrotra, Associate Professor of Medicine, Harbor-UCLA Medical Center, Torrance, California, investigators evaluated the safety and efficacy of lanthanum carbonate in doses of up to 4500 mg/day. In the first part of the study, patients were titrated up to 3000 mg/day for four weeks as required for serum phosphorus control. One cohort (A) continued on open-label 1500 to 3000 mg/day if they had achieved K/DOQI targets in the initial four-week phase while a second cohort (B) carried on in a forced-dose titration if not at target after the initial phase, at which point they received up to 4500 mg/day of lanthanum carbonate.

As Dr. Mehrotra reported, 54% of patients achieved the K/DOQI serum phosphorus target of 5.5 mg/dL (1.78 mmol/L) or lower at the end of four weeks at a dose of 3000 mg/day or less. Mean serum phosphorus levels remained at or below K/DOQI targets through to week 24 in the same cohort (A).

By week 8, 25% of those patients who had not achieved target serum levels by week 4 reached them by week 8 on 3000 mg/day, as did 38% of patients receiving 3750 mg/day and 32% of those receiving 4500 mg/day. In the overall cohort, two-thirds of patients achieved control on 3000 mg/day or less by week 8, investigators told delegates. Serum calcium, PTH and the calcium x phosphorus product remained within K/DOQI guidelines from the fourth week until study end.

Lanthanum carbonate was well tolerated, as investigators observed, and there was no increase in adverse events between its standard doses and the highest doses used in the study.

Summary

The average stage V CKD patient requires between six and 10 medications a day for optimal disease management and compliance with medical regimens in general is difficult. When it comes to treating hyperphosphatemia, one of many elements that require medical management in CKD, it is important not to add to the calcium burden unnecessarily, as calcium binders have been shown to increase vascular calcification and CAD risk. Both calcium binders and sevelamer are also associated with a large pill burden which potentiates non-compliance. High-dose lanthanum carbonate does not add to the calcium burden and it can control serum phosphorus in most patients with one tablet, taken three times a day with meals. This regimen clearly simplifies phosphate control and should enhance compliance.

Note: At the time of printing, lanthanum carbonate is not available in Canada.