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.

45th Annual Congress of the European Renal Association (ERA)/European Dialysis and Transplant Association (EDTA)

Stockholm, Sweden / May 10-13, 2008

In a review of 44 studies relevant to disorders of mineral metabolism, Dr. David Goldsmith, Guy’s Hospital, London, UK, observed that the risk of all-cause mortality was greatest in patients with elevations in phosphorus concentration. This was followed by elevations in serum calcium, with elevations in parathyroid hormone (PTH) being associated with the third highest risk of all-cause mortality.

Specifically, 21 studies evaluated hyperphosphatemia and each one of these studies identified a significant risk of all-cause mortality related to elevated phosphorus levels. Thirteen studies evaluated the risk of all-cause mortality and elevated serum calcium levels and of these, eight found a significant association. Of 11 studies observing all-cause mortality and elevations in PTH, six identified a significant risk. Threshold levels associated with a significant risk for all-cause mortality ranged from >5 mg/dL to >7.5 mg/dL for phosphorus, >8.8 mg/dL to >11.4 mg/dL for calcium, and >308 pg/mL to >600 pg/mL for PTH.

The calcium x phosphorus product was also assessed in 11 of the studies and in nine of them, a significantly increased risk of all-cause mortality was observed. Serum phosphorus levels, as well as the highest levels of PTH in excess of the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) targets, were also associated with significant cardiovascular (CV) risk, but not elevations in serum calcium.

Dr. Goldsmith indicated that the risk of all-cause hospitalization was significant with hyperphosphatemia (n=3), elevated serum calcium (n=1) and elevated PTH levels (n=1), although only a severe increase in PTH above the K/DOQI target of >600 mg/dL was associated with significant risk. In this group of studies, the threshold levels associated with a significant risk of all-cause hospitalization was >5 mg/dL to >7.5 mg/dL for phosphorus, >9.5 mg/dL for calcium and ³600 mg/dL for PTH.

“All studies showed a significant risk for parathyroidectomy with elevated phosphorus (n=3), calcium (n=2) and PTH levels (n=3),” Dr. Goldsmith reported. “The phosphorus, calcium and PTH cut-off levels above which the risk significantly increased were 4.5 mg/dL, 8.8 mg/mL and 38 pg/mL, respectively.” Dr. Goldsmith noted that none of the studies found changes in phosphorus or calcium levels were associated with a significant risk of fractures, although four out of six studies identified a significant risk for fractures with high as well as low PTH levels. Methodologies did vary across the studies.

Nevertheless, the studies confirmed that mineral abnormalities are significantly related to the risk of all-cause mortality, hospitalizations and parathyroidectomies and underscore the need to correct mineral abnormalities in dialysis patients.

Phosphate Binding in Early Disease

Substantial evidence has implicated hyperphosphatemia in the pathogenesis of vascular calcification which in turn may contribute to the high rates of CV morbidity and mortality seen in dialysis patients. As noted by Dr. Stuart Sprague, Professor of Medicine, Division of Nephrology/Hypertension, Northwestern University, Chicago, Illinois, vascular calcification is present not only in dialysis patients, but it is also often present in early CKD. Indeed, patients with CKD stage 3 and 4 are more likely to die than progress to dialysis, and they therefore may benefit from treatment with a phosphate binder to decrease overall phosphate burden that may contribute to early mortality.

The novel lanthanum carbonate is an effective non-calcium phosphate binder that binds to dietary phosphate in the gastrointestinal (GI) tract so phosphate is unable to pass into the bloodstream, thereby reducing overall phosphate absorption from the diet. As are other phosphate binders, lanthanum carbonate is used in dialysis patients but its effect in CKD 3 and 4 patients has not been widely studied. To that end, Dr. Sprague and colleagues randomized 119 patients with CKD 3 and 4 to either the active treatment at a starting dose of 750 mg or to placebo for a treatment interval of eight weeks.

Patients were entered into the phase II study if they had a serum phosphate level in excess of 1.49 mmol/L and lanthanum carbonate was titrated up to achieve a serum phosphate objective of less than 1.49 mmol/L. The intent-to-treat (ITT) population consisted of 90 patients and 71 patients completed the eight-week study.

After eight weeks of therapy, the majority of patients were receiving 3000 mg of lanthanum carbonate, as Dr. Sprague reported. On this dose, 44.6% of patients receiving lanthanum carbonate and 26.5% in the placebo group achieved a serum phosphate level of £1.49 mmol/L—the primary end point of the study. Although not statistically significant, the patients in the lanthanum carbonate group had a significantly (P=0.02) greater reduction in mean serum phosphate from baseline than did the individuals on placebo (Figure 1). Changes in urinary phosphate excretion from baseline were also significantly greater in the active treatment group compared to placebo controls (P=0.04), while serum intact PTH (iPTH) decreased by 23.8 ng/L from baseline in the lanthanum carbonate group. In contrast, iPTH increased by 8.8 ng/L in placebo controls (P=0.02).

Figure 1. Phosphate Burden at Eight Weeks

“Our study, along with others, suggests that serum phosphate is a late and insensitive marker of phosphate burden in CKD patients not requiring dialysis,” Dr. Sprague told delegates. “In such patients, serum phosphate concentrations should not be considered in isolation, but with other markers of disordered mineral metabolism such as urinary phosphate excretion, calcium x phosphate product and PTH. In our study, serum phosphate, urinary phosphate and PTH measurements all indicated that lanthanum carbonate reduces phosphate burden and offers a potential treatment option for preventing phosphate absorption in patients with CKD stages 3 and 4.”

Dr. Sprague acknowledged that none of the currently available phosphate binders are licensed for patients not receiving dialysis, even though many nephrologists use them in their practice for earlier-stage CKD patients. He remarked that each of the phosphate binders has its strengths and weaknesses; aluminum-containing binders, for example, are highly potent but they are associated with substantial toxicity, most notably abnormalities in bone; calcium-containing binders are widely available and inexpensive but they are associated with an increased risk of hypercalcemia.

The newer calcium-free phosphate binders, lanthanum carbonate and sevelamer hydrochloride, can lower serum phosphate levels without directly increasing the calcium load.

Studies to date with lanthanum carbonate indicate it is both well tolerated and has an excellent safety profile, although more long-term studies are needed to ensure it is not associated with long-term toxicity. The key advantage to using lanthanum carbonate rests in its potency which is comparable to aluminum-containing phosphate binders.

A single tablet of lanthanum carbonate with each meal also provides as much phosphate-binding potential as seven to 10 pills a day when using sevelamer. As Dr. Sprague noted, the average dialysis patient takes about 20 pills daily and the average patient with CKD takes 10 to 15. A phosphate binder that minimizes total pill burden could be expected to improve adherence to the phosphate binder regimen. For example, among patients enrolled in lanthanum carbonate studies who were previously treated with calcium, sevelamer or combinations, the use of lanthanum carbonate achieved reductions in pill consumption by 50% if they had been taking a combination of phosphate binders, by 32% if they had been taking sevelamer and by 25% if they were switched from a calcium-based binder, as Dr. Sprague observed.

For most patients with hyperphosphatemia, one 1000-mg tablet t.i.d. with each meal is enough to control most elevations in serum phosphate. A reduced pill burden also has potential to improve patient compliance to phosphate binder therapy, and improved adherence should translate into more consistent and more profound reductions in hyperphosphatemia and with them, a reduced risk of vascular calcification.

Calcium x Phosphate Product

A parallel study in the same group of patients evaluated by Sprague et al. also found that lanthanum carbonate effectively reduced the calcium x phosphate product in early-stage CKD. As observed by Dr. William Finn, University of North Carolina Kidney Center, Chapel Hill, a calcium x phosphate product in excess of 3.47 mmol2/L2 is the optimal value for predicting the presence of vascular calcification. At baseline, the mean calcium x phosphate product in the lanthanum carbonate group was 3.76 mmol2/L2 and 3.88 mmol2/L2 in the placebo arm. Even by week 4, the same regimen of lanthanum carbonate, started at 750 mg a day and titrated up to 3000 mg, had produced significantly greater reductions in mean calcium x phosphate product of 0.43 mmol2/L2 than placebo at 0.16 mmol2/L2. By week 8, the difference in calcium x phosphate product between the two groups at 0.35 mmol2/L2 for lanthanum carbonate vs. 0.15 mmol2/L2 for placebo was no longer statistically significant, even though there were slight increases in serum calcium in the lanthanum carbonate group.

As discussed by Dr. Alastair Hutchison, Clinical Director, Renal Unit, Royal Infirmary, Manchester, UK, it is widely appreciated that phosphate metabolism is central to the process of mineral homeostasis. For example, the consequences of hyperphosphatemia include CV and other metastatic calcifications, as he indicated.

However, changes in phosphate load in early CKD may not be accurately reflected by serum phosphate levels, as in patients not yet on dialysis, the kidney is often still able to control serum phosphate levels through an increase in serum PTH, reduced synthesis of active vitamin D and up-regulation of fibroblast growth factor 23 (FGF23). “Together, [these mechanisms] enhance renal excretion of phosphate and decrease its absorption from the GI tract,” Dr. Hutchison told delegates.

A direct causal relationship between phosphate and vascular calcification has not yet been proven, as Dr. Hutchison noted. Nevertheless, it is quite evident that phosphate makes an important contribution to vascular calcification. Dr. Hutchison stated, “We view CKD as a continuum, that patients progress through stages 3, 4 and 5 onto dialysis and perhaps transplantation. If we can control serum phosphate early in CKD, perhaps we can influence vascular calcification, and if we can, we may influence mortality.”

Prevention of Vascular Calcification

Recent animal studies have demonstrated an important link between phosphate levels and vascular calcification and researchers now seek to determine whether treatment with a non-calcium-containing phosphate binder can prevent vascular calcification.

In a study reported here by Dr. Ellen Neven, University of Antwerp, Belgium, and colleagues, investigators evaluated whether lanthanum carbonate could prevent vascular calcification in uremic rats with adenine-induced chronic renal failure. Male Wistar rats were randomly assigned to one of three diets after two weeks on a high-phosphate diet: 1% lanthanum carbonate (1% group), 2% lanthanum carbonate (2% group) or 2% cellulose (control group) for six weeks. “Adenine feeding induced moderate to severe chronic renal failure in all groups, with serum creatinine around 2 mg/dL,” Dr. Neven reported.

Treatment with 1% lanthanum carbonate did not significantly reduce vascular calcification parameters, but in the 2% group, vascular calcium content, as well as area percentage von Kossa positivity in aorta, were significantly reduced in comparison with the 1% group, as she noted. “Both aorta calcium content and calcified volume were significantly reduced in the 2% cohort, and in this group [of animals], vascular calcification was observed in only one animal. Median calcium content was 0, whereas median calcium content of 2.4x106 and 2.8x106 arbitrary units were observed with this technique in the control and 1% groups, respectively” (P=0.01 vs. control and P<0.01 vs. 1%).

Since patients with end-stage renal disease have a high CV mortality risk, lanthanum carbonate as a non-calcium-containing phosphate binder may be a promising alternative to those that contain calcium in patients with an elevated calcium x phosphorus product or hypercalcemia, she observed.

In turn, Dr. Ioannis Kakavas, Hippokration General Hospital, Athens, Greece, demonstrated that both sevelamer hydrochloride and lanthanum carbonate controlled serum phosphorus in patients on peritoneal dialysis without inducing hypercalcemia or increasing the calcium x phosphorus product. Both agents were also shown to be safe and well tolerated, but patient compliance was better with lanthanum carbonate because the pill burden is substantially less with lanthanum carbonate than with sevelamer, as he noted.

Among the new factors that may affect management of CKD is FGF 23. As reported by Dr. Markus Ketteler, Chief, Division of Nephrology, Coburg Academic Teaching Hospital, University of Würzburg, Germany, FGF 23 leads to increased renal phosphate excretion and inhibits the 1 alpha-vitamin D3 hydroxylase that reduces levels of active vitamin D metabolite. This in turn decreases intestinal absorption of phosphate.

FGF 23 is likely triggered and upregulated by hyperphosphatemia, then returns to the kidney where it functions as a highly potent phosphaturic hormone. FGF 23 also suppresses calcitriol synthesis which contributes to PTH secretion. As PTH is also a strong phosphaturic hormone, it also goes back to function in the kidney. In experimental animals who have had FGF 23 genetically removed, Dr. Ketteler and colleagues demonstrated that the mice become malnourished and died because both hyperphosphatemia and hypervitaminosis D occured and calcitriol levels rose dramatically. “It is a very sophisticated feedback system to just keep the phosphate down,” Dr. Ketteler remarked.

Summary

High serum phosphate levels are implicated in the development of vascular calcification, which may in part explain the high rates of CV morbidity and mortality in dialysis patients. The question many nephrologists are now asking is whether earlier introduction of phosphate binders can reduce the phosphate burden enough to reduce the risk of vascular calcification and subsequent CV morbidity and mortality. Several studies presented here support an effect on serum phosphate levels in patients with CKD stage 3 and 4 treated with the non-calcium-containing phosphate binder lanthanum carbonate. The compound was also well tolerated and at the lowest pill burden of all phosphate binders, has the potential to improve compliance and with it, lead to more consistent reductions in phosphate levels and a lower phosphate burden over time.