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UPLIFT: New Data Reinforces a Maintenance Algorithm

Improving Phosphate Control in Patients with Chronic Kidney Disease

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.

MEDICAL FRONTIERS - World Congress of Nephrology

Milan, Italy / May 22-26, 2009

Life expectancy for dialysis patients is comparable to that of patients with ovarian cancer, considered to have among the poorest prognoses of all cancers. Perhaps even more sobering is US data showing that patients with stage 3 to 4 chronic kidney disease (CKD) are 20 times more likely to die than proceed to dialysis.

In the opinion of Dr. Geoffrey Block, Director of Clinical Research, Denver Nephrology, Colorado, this is partly due to inattention to phosphate control in early-stage CKD. Even though serum phosphorus is an insensitive marker of phosphate homeostasis, “we should strive to maintain a serum phosphorus at <1.13 mmol/L in everybody,” he stressed, “difficult as it may be.”

As Dr. Block noted, current guidelines indicate that physicians should intervene when serum phosphate levels exceed 4.6 mg/dL (1.48 mmol/L). Those guidelines, however, effectively mean that physicians do nothing about serum phosphorus until CKD patients are close to requiring dialysis. In the meantime, levels have been increasing for years before physicians start to worry about them—far too late, in Dr. Block’s view, as alterations in phosphorus homeostasis are important mediators for the adverse cardiovascular (CV) events that disproportionately contribute to premature mortality in all CKD patients.

“It’s my belief that as we allow phosphorus to increase for years during the early stages of CKD, we are promoting the development and the progression of vascular calcification [because] as you lose kidney function, you can detect calcification in a higher and higher proportion of patients,” Dr. Block explained.

In fact, even when serum phosphorous levels remain within the normal range, severe coronary calcification has been shown to occur in pre-dialysis patients.

In animal models of CKD, extensive calcification in animals fed a high fat diet can be completely prevented by reduction in phosphate levels through the use of any phosphate binder—both calcium and non-calcium-based as Dr. Block indicated.

At the moment, guidelines do not recommend reductions in serum phosphate levels of 1.13 mmol/L, as Dr. Block is advocating. But the literature consistently supports this threshold as an important cut-off point above which morbidity events start to occur. In one large study of approximately 4000 patients with CVD, “there was a statistical increase in the risk of any CV event as the phosphorous levels rose above 1.13 mmol/L,” Dr. Block reported. “Almost identical” results were seen in CKD patients, where as soon as serum phosphorus levels exceed 1.13 mmol/L, “we see the same relationship [with morbid events] as we showed in dialysis patients 13 years ago but now we see at levels of 1.13 mmol/L in patients not on dialysis.” he added.

Among healthy young adults in the Framingham cohort who were followed for 20 years, researchers documented a 50% increase in the risk of a first vascular event at serum phosphorus levels in excess of 1.13 mmol/L, he noted, while post-hoc analysis of the ABCD trial in type 2 patients demonstrated the same threshold phenomenon. As Dr. Block remarked, guidelines also indicate that patients must restrict their intake of dietary phosphorus to control serum phosphorus levels. But as he pointed out, patients also need protein. “If you look at the relationship between protein intake and phosphorus, you see it is impossible to control phosphorus to <800 mg a day and still take in enough protein,” Dr. Block said.

Furthermore, a recent study of dialysis patients showed that patients who decreased their protein intake had higher mortality rates regardless of whether their serum phosphorus rose or fell. “It’s only patients whose protein intake went up and whose phosphate levels went down who had a survival advantage and this is what we need to do,” Dr. Block observed.

Integrated Systems

The extent of the skeletal and vascular systems' integration was described by Prof. Jorge Cannata-Andía, Professor of Nephrology, University of Oviedo, Spain. In the absence of CKD, the skeleton serves as the main store for phosphate; in its presence, phosphate load increases and the ability of bone to serve as a phosphate reservoir is compromised. Because extracellular phosphate cannot be sequestered by bone, “soft tissues act as the alternative store for excess mineral, leading to the ossification of vascular tissue,” Prof. Cannata-Andía explained.

This relationship has been demonstrated in the general population where studies have shown that the higher the aortic calcification score, the lower the bone mass. In a CKD population, the age-related tendency for vascular calcification to increase and bone mineralization to decrease is significantly exacerbated, such that the greater the aortic calcification scores in one study of dialysis patients, the lower the bone mineral activity. In a number of CKD studies, low bone mineralization is associated with an increase in fragility fractures, as it is in the general population.

The vascular system is subject to many promoters of calcification, as Prof. Cannata-Andía pointed out, one of which is serum phosphorus. In an animal model fed a diet containing 50% greater amounts of phosphorous than usual, investigators observed intense calcification in the aorta after only 20 weeks of the phosphate-enhanced feed. Epidemiological studies in CKD populations have also consistently implicated serum phosphorus as an important contributor to vascular calcification and mortality. Consequently, reductions in serum phosphorus have the potential to decrease vascular calcification risk and, potentially, enhance life expectancy, as Prof. Cannata-Andía suggested.

To date, no significant differences in mortality rates have been observed between calcium-based and non-calcium-based binders. However, in the subgroup analysis Dialysis Clinical Outcomes Revisited (DCOR) investigators observed a 22% reduction in all-cause mortality in patients 65 years of age and older who received sevelamer compared with a calcium-based binder. Similarly, a subgroup analysis of patients 65 years of age and older enrolled in another comparative study showed that after a mean of about two years, all-cause mortality rates for patients aged 65 and older were 31% lower for those who received lanthanum carbonate compared with standard therapy.

Concluded lead author Rosamund Wilson, PhD, Spica Consultants Ltd., Marlborough, UK, “Extensive epidemiological data link elevated serum phosphorus levels with increased mortality, and effective serum phosphorus control, particularly with non-calcium-based phosphate binders, may reduce the risk of vascular calcification, potentially improving clinical outcomes in CKD patients.”

Phosphate Balance

As noted by Dr. Edward Ross, Associate Professor of Medicine, University of Florida, Gainesville, estimates of phosphate balance in dialysis patients indicate that for a 70-kg patient, there is a net surplus of about 360 mg phosphorus/day—“which is what we have to bind with our binder,” he remarked. Heavier patients will almost certainly consume more dietary phosphorus, he added, and therefore have that much more serum phosphorus to be bound.

Comparing the chemistry of the two non-calcium phosphate binders, Dr. Ross noted that it is “generally not appreciated” that some phosphate binders depend on the pH of the environment to effectively bind.

According to Dr. Ross, sevelamer has a relatively low affinity to bind in the stomach or the early small intestine where the pH is low, binding best at a pH of 7. In contrast, lanthanum carbonate binds across the range of pH—a fact that may be very important clinically as phosphate additives in food are absorbed early on at a time when the pH is likely low. From additives alone, patients can consume over 500 mg of phosphorus a day—indeed, as much from additives as from a low-protein diet. “Binders that require high pH would therefore be less effective,” he stated. As noted here at the scientific sessions, sevelamer also becomes a better binder when it is incubated in a high pH environment. Again, this is relevant for patients who have little to no gastric acidity due to medical blockade, he added.

Stability is another chemical property that can affect clinical performance. Although sevelamer does lower LDL-C—a desirable feature—it must bind competitively with bile acids, thereby potentially compromising its ability to bind with phosphate. In contrast, lanthanum carbonate binds very tightly with phosphate and competitive binding does not occur.

Even if both the affinity and stability of a phosphate binder are high, “if the potency is weak, the pill burden would be so high that we would never control phosphate because there would be so much non-compliance,” Dr. Ross observed. Investigators here at the WCN examined the potency of phosphate binders in animal models using urinary phosphate excretion rates as a measure (the more potent the phosphate binder, the less will appear in the urine). The same doses of the three different elemental binders showed that urinary phosphate excretion was greatest with sevelamer, followed by a calcium-based binder, with virtually no urinary phosphate detected for lanthanum carbonate.

Study Findings

A study was carried out in which patients with a serum phosphorus of at least 6.0 mg/dL (1.94 mmol/L) at baseline and a calcium of at least 8.4 mg/dL (2.1 mmol/L) were randomized to either lanthanum carbonate or sevelamer for four weeks, after which they were switched to the alternative binder for an additional four weeks. Importantly, as Dr. Ross observed, this was a fixed-dose protocol, so patients were initially treated with standard starting doses of each binder for one week: 2250 mg lanthanum carbonate and 4800 mg sevelamer, after which the dose was escalated to 3000 mg lanthanum carbonate and 6400 mg for sevelamer for the remaining three weeks.

The most “clinically relevant” analysis involved patients who had the full four-week course of each phosphate binder: In this analysis, serum phosphorus was 0.50 mg/dL (0.16 mmol/L) lower at the end of treatment with lanthanum carbonate compared with sevelamer, which was statistically significant (P=0.007). Similarly, the difference between on-treatment serum phosphorus values were 0.41 mg/dL (0.13 mmol/L) lower when patients were taking lanthanum carbonate in the observed cases for the intent-to-treat population (P=0.028) (observed cases for this population presented all available data at each time point).

The only analysis that did not show a statistical difference between the two treatments was the last observation carried forward analysis (LOCF), where the last value of serum phosphorus was carried over from the point where patients dropped out, even if the dose was never escalated, as Dr. Ross pointed out. In this LOCF analysis, patients on lanthanum carbonate still had a greater than 0.29 mg/dL (0.09 mmol/L) reduction in their serum phosphorus compared to sevelamer but this did not reach statistical significance (Figure 1).

Figure 1.


“The reduction in serum phosphate was greater at every interval with lanthanum carbonate than with sevelamer and it was statistically significantly greater at week 1 with the lower dose as well as at week 4 with the higher dose,” Dr. Ross added. The drop in serum phosphorus with lanthanum carbonate was also more rapid than it was for sevelamer and it was also sustained across the four weeks of treatment.

In contrast, between week 3 and week 4, serum phosphorus levels started to increase with sevelamer, indicating that at the fixed dose of 6400 mg/day, serum phosphorus was not optimally controlled (Figure 2).

The adverse event profile of both binders was very similar, as Dr. Ross observed. As he also noted, a 0.5 mg/dL greater reduction in serum phosphorus as achieved with lanthanum carbonate over sevelamer may not seem clinically significant. However, many studies have underscored the clinical relevance of a 0.5 mg/dL decrement or increment in serum phosphorus, showing a lower or higher relative risk of death at ev
nces.

Figure 2.

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“The differences seen in this study in serum phosphorus are therefore not only statistically significant, they are clinically important as well,” Dr. Ross concluded.

Questions and Answers

The following section is based on discussions with Dr. Geoffrey Block, Director of Clinical Research, Denver Nephrology, Colorado and Dr. Edward Ross, Associate Professor of Medicine, University of Florida, Gainesville.

Q: Do you think phosphate binders will have a greater impact on mortality than vitamin D analogues?

Dr. Block: I think it is premature to think that vitamin D affects outcomes. But do I think phosphate control will have a greater impact on outcomes? I absolutely do. Q: In the trial of sevelamer and lanthanum carbonate, patients did not reach the optimal goal of 1.13 mmol/L as advocated by Dr. Block. How can we reach this goal?

Dr. Ross: This was not part of the design of the trial but maybe looking at a binder’s capacity will give you a better handle on what dose of the tablet and pill burden will be necessary to lower phosphorus to a given level. Both of these binders have been used at much higher doses than were used in this study and that is what we are seeing in clinical practice as well.

Dr. Block: My comments regarding target serum phosphorus levels of 1.13 mmol/L were for CKD 3 and 4 patients only, even though I believe 1.13 mmol/L is the right target for everybody. If we want to control serum phosphorus in dialysis patients, we need more dialysis. That is the absolute best way to control serum phosphorus. In addition, I think companies should tell us how much phosphorus is in food. Right now, phosphorus is added to everything and we will never control phosphorus until we have some idea what our phosphorus intakes really are.

Q: Would the differences in the chemistry between the two binders explain the loss of phosphorus control with sevelamer that you saw at the end of four weeks?

Dr. Ross: I don’t think it would account for any of the late effects. To be fair, it may be just a statistical quirk so we have to figure that out. But I think the chemistry behind the binders does suggest there may be more variability in phosphate binding with sevelamer. That said, I use both drugs and I think it’s just comforting to know we have a safe drug that is at least as good and in some cases better than what we’ve been using before and that we can now add it to our armamentarium.

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