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Controlling Hyperphosphatemia 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 - 2010 Congress of the European Renal Association and European Dialysis and Transplant Association (ERA-EDTA)

Munich, Germany / June 25-28, 2010

There are now several sets of data that associate sustained control of serum phosphorus (SP) levels with a reduction in mortality among patients who require chronic dialysis therapy. An outcome advantage may also be gained by SP control in patients with advanced chronic kidney disease (CKD) even before chronic dialysis is required. However, the critical step is treating to goal without introducing new complications, such as calcium overload. Non-calcium-containing agents are increasingly recognized as critical in the attempt to achieve an acceptable benefit:risk ratio.

“As a consequence of CKD-mineral and bone disorder (CKD-MBD), more than 80% of patients on dialysis suffer from osteopathy and cardiovascular calcifications. Disorders of mineral metabolism, in particular an elevated SP and increased serum calcium, are major risk factors for these diseases. Both are associated with an increased mortality,” stated Dr. Frank Dellana, Nephrology Center Karlstrasse, Düsseldorf, Germany, here at the ERA-EDTA congress. He presented data on the non-calcium-containing lanthanum carbonate from 698 patients treated at 116 dialysis centres and reported that most patients (89%) had received a different phosphate binder previously.

“Lack of efficacy of the previous therapy was the reason for change in 78.5% of these patients. On previous therapy, mean SP levels had been 2.33 mmol/L (7.21 mg/dL). On lanthanum, the mean SP levels fell to 2.04 mmol/L (6.32 mg/dL) within 2 weeks, which was a statistically significant reduction (P<0.05). After 6 months, the mean SP decreased to 1.93 mmol/L (6.0 mg/dL) (P<0.0001),” Dr. Dellana told delegates. Although adverse events were reported in 7.6% of patients, only about 20% of events were considered drug-related. The types of adverse events, mostly gastrointestinal (GI)-related, were consistent with those observed in previously published randomized trials. Dr. Dellana concluded that these data confirm the efficacy and tolerability of lanthanum in a real-world treatment setting: “In this study, a significant reduction of SP was observed after change of therapy to lanthanum carbonate, a non-calcium, non-resin phosphate binder.”

Non-calcium-Containing Phosphate Binders

The ability of non-calcium-containing phosphate binders to reduce SP without substantially increasing calcium levels is now recognized as critical for reducing the cardiovascular risk associated with vascular calcification, but phosphate binders that share the non-calcium-containing characteristic can be differentiated for other relevant variables, such as ability to preserve protein intake.

“Data from patients on dialysis suggest that increasing protein intake while reducing SP is associated with a lower risk of mortality compared with concurrent increases or decreases in both parameters, or a decrease in protein intake with an increase in SP. Therefore, highly effective phosphate binders may be desirable to treat elevated SP while allowing increased protein intake in patients with CKD on dialysis,” reported a team of investigators who presented comparative data on phosphate binders here at the ERA-EDTA meeting. This observation was relevant because their comparison between lanthanum carbonate and sevelamer carbonate found lanthanum to produce almost twice the level of phosphorus binding even though it was administered at a lower dose.

“These data suggest that in clinical practice, lanthanum carbonate may be a more effective phosphate binder than sevelamer carbonate,” reported the investigating team, which involved a collaboration of investigators in the US and the UK. They suggested the data are important because greater efficacy at phosphate binding would permit greater dietary protein intake.

Findings from Crossover Studies

In this randomized, crossover study, healthy volunteers underwent a series of treatment periods separated by washouts of 7 to 14 days. Initiated with a fasting, the study periods consisted of a meal alone, a meal plus 1000 mg lanthanum or a meal plus 2400 mg sevelamer (Figure 1). The order of these was random in the 18 participants. Plasma-optical emission spectroscopy was used to analyze the phosphorus content of the rectal effluent after the meals.

Figure 1.


On lanthanum carbonate, 135.1 mg (±12.3 mg) of phosphorus was bound vs. only 63.2 mg (±12.3 mg) on sevelamer carbonate. The difference of 71.9 mg was highly significant (P<0.001) and would be expected to increase the likelihood that patients on lanthanum carbonate could maintain protein intake relative to those on sevelamer carbonate if treatment was started at the same level. A published crossover study has previously demonstrated that lanthanum carbonate produces a greater reduction in SP levels when patients complete four weeks of treatment (Sprague et al. Clin Nephrol
e 2).

Figure 2.

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The drugs did not differ on an intention-to-treat analysis in this study because only about two-thirds of the patients completed therapy after the crossover. However, the 0.5 mg/dL (0.16 mmol/L) greater reduction in SP on lanthanum carbonate relative to sevelamer carbonate among those who did complete the study was highly statistically significant (P=0.007). While the greater efficacy of lanthanum is consistent with its greater phosphate binding, this was one of several differences identified in studies presented here at the ERA-EDTA congress.

Effects on Calcitriol

In another crossover study, the effects of lanthanum carbonate and sevelamer were compared on the pharmacokinetics of the oral vitamin D supplement calcitriol. Again, there was a random sequence of study periods in healthy volunteers who received oral calcitriol alone, oral calcitriol with lanthanum carbonate, and oral calcitriol with sevelamer carbonate. An advantage for lanthanum was predicted because sevelamer is known to have a high affinity for bile salts and is therefore prone to inhibit calcitriol metabolism.

Indeed, lanthanum carbonate had no significant effect on oral calcitriol bioavailability when compared to baseline levels (Table 1), whereas sevelamer carbonate reduced calcitriol bioavailability by 55% with a highly significant reduction in the maximum concentration (Cmax) relative to calcitriol alone (P<0.001). These data are relevant because vitamin D is
the risk of hyperparathyroidism in CKD patients.

Table 1.

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Overall, the management of elevated serum phosphate requires careful consideration of the benefit:risk ratio due to actions of phosphate binders on important additional mediators of health risk. This includes SP levels, calcium levels, calcitriol levels and calcium-phosphorus product.

In a study conducted in Spain, the authors attempted to track all of these changes over one year in 77 dialysis patients started on lanthanum. Prior to starting lanthanum, 51.9% of the patients were on a phosphate binder that produced calcium chelation and 48.1% were on the non-calcium agent sevelamer. On lanthanum, there were substantial reductions in SP and in calcium-phosphorus product. “With lanthanum carbonate, a higher number of patients showed osteodystrophy biochemical parameters within recommended ranges,” reported Dr. José Lacueva, Centro Cediat-Llíria, Valencia, Spain. “Lanthanum carbonate has succeeded in reducing the use of calcium-based agents and sevelamer with the virtual disappearance of aluminium hydroxide binders.”

Pre-dialysis Patients

In general, studies of phosphate binders have been concentrated in patients on dialysis, but data presented at the ERA-EDTA meeting suggest that a high proportion of CKD patients go on this therapy even before dialysis, but like dialysis patients, they are often not treated to an appropriate target.

In a study presented by a cooperative investigating team from Shire Pharmaceuticals, Genzyme Corporation and Fresenius Medical Care, data from 2193 patients with a diagnosis of CKD and recorded measures of both SP and parathyroid hormone (PTH) were evaluated. Patients on dialysis were excluded.

“Initiation of phosphate binder therapy often occurred when SP and PTH levels were well above the normal range,” reported the senior author of the study, Dr. Michael Keith, Shire Pharmaceuticals, Wayne, Pennsylvania. He noted that over the three years of data collection, treatment with phosphate binders appeared to be offered earlier in the course of renal disease progression. For example, the mean creatinine value at the time of phosphate binder initiation in the first year was 5.9 mg/dL (1.91 mmol/L) but declined to 4.6 mg/dL (1.49 mmol/L) by the third year. Similarly, the mean estimated glomerular filtration rate at the time of phosphate binder initiation in the first year of study was 13.1 mL/min but increased to 17.0 by the last year.

These results are encouraging and appear to reflect a growing awareness of the importance of phosphate binders in patients with declining renal function, but it is possible that even more aggressive treatment could offer a further advantage relative to long-term outcome. Importantly, early treatment does not appear to risk diminished effect over time. In an analysis that pooled data from several long-term studies, with the longest follow-up extended to six years, there was no evidence of a diminished effect over time with the phosphate binder lanthanum carbonate. In fact, the reduction over several years was almost exactly the same as the reduction achieved by 90 days. These data were considered important because of a previous study that demonstrated that the mortality reduction achieved with phosphate binders is dependent on a sustained indefinite effect.

A rapid reduction in SP may also be important for improved outcome, particularly in patients who have not been previously treated or who have advanced disease with a sustained SP level far above target. Among the relative advantages of lanthanum for a high degree of phosphorus binding without adverse effects on other parameters, such as calcium overload or oral calcitriol bioavailability, it also appears to be rapid. An analysis reported here at the ERA-EDTA pooled data from four studies with 437 stage 5 CKD patients and was designed to look specifically at speed of effect. Significant reductions in SP were observed within one week of starting treatment.

However, the efficacy of currently available agents is only relevant when patients are assessed appropriately and routinely for SP and PTH levels so that appropriate therapy can be introduced and titrated to reach treatment targets. Current options indicate that effective and sustained control of SP can be achieved with a favourable benefit:risk ratio in dialysis patients and in patients with advanced CKD who can benefit from protection against hyperphosphatemia.

Summary

A series of studies presented here at the ERA-EDTA congress reinforce previous evidence that non-calcium-containing phosphate binders differ in ways likely to be meaningful to outcome. In comparative studies, lanthanum offered greater binding of SP than sevelamer carbonate and, unlike sevelamer carbonate, did not adversely affect oral calcitriol bioavailability. However, the relative advantages of this therapy can only be realized in patients whose hyperphosphatemia is recognized and treated to target. There is a delicate balance that defines an optimal benefit:risk ratio when attempting to reduce SP without increasing calcium or destabilizing other important metabolic factors, such as vitamin D. However, it is hoped that the differences between therapies will draw more attention to treating hyperphosphatemia overall to increase the proportion of patients reaching treatment targets.

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