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.

40th Annual Meeting and Scientific Exhibition of the American Society of Nephrology

San Francisco, California / November 2-5, 2007

As discussed by Dr. Francisco Llach, Division of Nephrology and Hypertension, Georgetown University Hospital, Washington, DC, high-calcium intake frequently leads to episodes of hypercalcemia, which have been related to the development of vascular calcification. Furthermore, high-serum phosphate levels are also systemically toxic and both high levels of phosphorus in patients with normal kidneys as well as hyperphosphatemia in chronic kidney disease (CKD) patients have been linked with increased cardiovascular (CV) risk.

In one study cited during a debate on the management of phosphorus in CKD by Dr. David Bushinsky, University of Rochester Medical Center, New York (Dhingra et al. Arch Intern Med 2007;167:879-85), it was observed that higher levels of serum phosphorus, though still within the normal range, were associated with increased CV disease risk at a mean of 16.1 years of follow-up in Framingham Offspring study participants who had no CKD or CV disease at baseline.

According to Dr. Rajnish Mehrotra, Harbor-UCLA Research and Education Institute, Torrance, California, the rate at which vascular calcification progresses has been repeatedly linked to worse outcomes. He addressed delegates, “So the question now is: Can you modify the rate of progression and will that modify outcomes?” As participants at the medical debate observed, more adequate dialysis is probably the most effective intervention by which to lower elevated phosphorus levels, but this is not an option for most dialysis patients.

Pharmacologic intervention is obviously an important strategy as well, noted Dr. Geoffrey Block, Denver Nephrology, Colorado. In Dr. Block’s view, physicians should not wait until serum phosphate levels exceed 5.5 mg/dL, target levels set by Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines for intervention. Instead, phosphate binder therapy should be initiated at any level of serum phosphorus above the normal range for the general population. The choice of a phosphate binder must be given due consideration, as speakers here agreed. This is particularly important in light of mounting evidence that calcium-based binders exacerbate vascular calcification compared with non-calcium formulations, and considering that the majority of dialysis patients are prone to calcify.

In the widely cited Treat-to-Goal study by Block et al. (Kidney Int 2002;62:245-52), 57 patients were randomized to sevelamer HCl and another 56 received either calcium acetate or calcium carbonate. Over the following 52 weeks, mean serum phosphorus levels were virtually identical in all groups and all achieved K/DOQI targets for CKD stage 5 patients. However, by study end point, the median change in the coronary artery calcium score (CACS) at 25% was significantly greater among calcium-based binder recipients than among sevelamer patients at 6%. The median change in the aortic calcium score was also significantly greater in calcium patients at 28% compared with 5% for those taking sevelamer. A recently published assessment of all-cause mortality as a secondary end point in that study also showed that treatment with sevelamer was associated with a borderline survival advantage compared with calcium-containing binders (Kidney Int 2007;7(15):438-41).

As again reported by Block et al., baseline CACS in patients new to dialysis in this follow-up study was a significant predictor of mortality at 66 months (P=0.002). Mortality was also numerically lower in those randomized to sevelamer at 5.2 deaths per 100 patient-years compared with 10.6 deaths per 100 patient-years in the calcium-containing binder arms, a difference of borderline significance between the two groups.

Nevertheless, when matching a phosphate binder to a CKD patient, “you can’t look at phosphate alone,” indicated Dr. Mehrotra. Rather, physicians need to consider the whole mineral metabolism milieu, including calcium levels, as well as levels of parathyroid hormone (PTH), before selecting a binder. In a patient that has a suppressed PTH or high calcium level or both, “to give that patient a calcium-based binder would be incorrect because it will worsen the situation,” according to Dr. Mehrotra. As well as in a patient with metabolic acidosis, “to give that patient sevelamer HCl would be a mistake as well,” he added.

There is also a need to recognize that not all CKD patients will calcify in response to binder therapy. As both Drs. Block and Mehrotra have documented, if patients show no evidence of calcification on initiation of hemodialysis, they are very unlikely to develop significant calcification over the course of the next several years.

On the other hand, “if you are a calcifier and I give you calcium, 95% of people get worse,” Dr. Block observed. To differentiate those patients who are “non-calcifiers” from the majority who are, Dr. Block recommended taking a cross-table lateral X-ray of the abdomen using the Framingham methodology. At approximately 75% sensitivity and specificity, people who have evidence of calcium at L1, L2 and L4 are likely to have a CACS by electron beam computed tomography of at least 30, indicating calcifier status, at which point, Dr. Block commented, “I would give them a non-calcium-containing binder.”

Other Mineral Abnormalities

Survival of hemodialysis patients may be indirectly driven by elevated levels of both calcium and phosphorus, as well as other mineral abnormalities associated with CKD, which might also play a role in adverse outcomes. Having previously reported an increased risk of all-cause mortality and high serum alkaline phosphatase levels in over 58,000 hemodialysis patients (Kidney Int 2006; 70:771-80), Dr. Kamyar Kalantar-Zadeh, Harold Simmons Center for Kidney Disease Research and Epidemiology, Torrance, and colleagues examined the link between high serum alkaline phosphatase and the risk for CV disease mortality.

As presented by Dr. Csaba Kovesdy of the same institute, researchers examined the association between total serum alkaline phosphatase and CV death over a period of three years in 82,049 hemodialyis patients enrolled from dialysis centres across the US. Alkaline phosphatase levels were divided into levels of less than 60 IU/L; 60 to 80 IU/L; 80 to 100 IU/L (reference levels) and 100 to 120, 120 to 140, 140 to 180 and 180 IU/L and above. Analyses were carried out in both unadjusted models as well as models adjusted for case-mix parameters and the malnutrition-inflammation complex syndrome.

Analyses based on all three models showed that total serum alkaline phosphatase levels were incrementally associated with increased CV death even after levels were adjusted for other clinical and laboratory measures, including intact PTH. Researchers also noted that interventions that decrease serum alkaline phosphatase might lessen the risk for CV disease and death in these high-risk patients.

Investigators under lead author Dr. Malik Touam, Centre ambulatoire Laënnec, Saint-Herblain, France, also reported that switching patients from sevelamer to lanthanum carbonate improved serum bicarbonate concentrations in a group of seven patients with metabolic acidosis.

For the study, Dr. Touam and colleagues collected data for a period of three months prior to making the switch to lanthanum carbonate and then for three months after patients had been switched. While on an average daily dose of sevelamer 6.4 g, serum bicarbonate levels were 24.2 mmol/L, serum phosphorus was 1.60 mmol/L and serum calcium 2.26 mmol/L. Average PTH levels were 351 pg/mL.

Following the switch to lanthanum carbonate, at an average daily dose of 0.93 g, serum bicarbonate increased significantly to 24.2 mmol/L (P<0.001), while serum phosphorus, serum calcium and serum PTH remained essentially unchanged. The average dose of calcium carbonate also dropped from 0.5 g/day while on sevelamer to 0.25 g when switched to lanthanum carbonate (P<0.001). “The increase in serum bicarbonate was not due to calcium carbonate but rather because of the consequences of lanthanum carbonate.” As Dr. Touam acknowledged, the study was clearly limited in size. Nevertheless, investigators felt that their study “strongly suggests” that lanthanum carbonate is effective at reducing elevated phosphorus levels without inducing a worsening of metabolic acidosis in patients who developed it on sevelamer HCl.

Enhancing Compliance

With optimal compliance, no phosphate binder has been shown to be superior to any other in terms of achieving adequate phosphate control, speakers here agreed. At the same time, they also concurred that compliance to binder therapy is frequently suboptimal and efforts need to be made to improve access to newer phosphate binders and in understanding the importance of taking phosphate binders as prescribed.

In a pilot study investigating compliance to phosphate binder therapy, Monique Elseviers, PhD, Department of Nursing Sciences, University of Antwerp, Belgium, and colleagues followed a cohort of 68 patients over a period of 15 weeks. Patients had been on hemodialysis for about four years and all patients except one were on calcium carbonate. Thirty-two patients also took concomitant sevelamer and four took concomitant lanthanum carbonate. Overall, the cohort ingested a mean of 6.5 pills of day of binder therapy alone and the majority of them were taking their binder therapy three times a day. Using an electronic monitoring system with MEMS-V Track-Cap devices (one MEMS per phosphate binder), investigators developed a computerized compliance report for each patient over the 15 weeks of follow-up.

Defining non-compliance as taking less than 80% of prescribed doses, “we found that approximately 30% of patients could be identified as non-compliers using this MEM tracking device,” Dr. Elseviers reported. In almost one-third of registered days, 32% of doses were omitted and in 8% of registered days, no medication was taken, the worse days for compliance being Wednesdays and Sundays, she added.

Interestingly, no difference in compliance rates could be observed between first- and second-generation phosphate binders. Nor was there a significant difference in serum phosphorus levels between compliers at a mean of 4.8 mg/dL vs. a mean of 5.1 mg/dL for the non-compliers, although as Dr. Elseviers noted, even when patients did comply, “we still had a group of patients who had mean serum phosphorus levels that were too high.”

In the meantime, increasing attention is being paid to the treatment of hyperphosphatemia in earlier stage CKD 3 and 4 disease. In a randomized, multicentre trial involving 225 CKD patients with an estimated glomerular filtration rate (eGF) of between 15 and 59 mL/min/1.73 m2, Dr. Stuart Sprague, Northwestern University Feinberg School of Medicine, Chicago, Illinois, and colleagues identified 29% of them as CKD stage 3, 66% as stage 4, and the remaining 5% as stage 5, although they were not on dialysis. At screening, 80% of the cohort was naive to phosphate binder therapy, despite the fact that 45% had elevated serum phosphorus levels of at least 4.6 mg/dL.

At the same time, 71% of patients had an elevated PTH of at least 65 pg/mL (mean 127 pg/mL). Of those with vitamin D data, the great majority were deemed to have insufficient or deficient levels of the various vitamin D constituents. “These data indicate that elevated serum phosphorus is quite prevalent in patients with CKD stages 3 and 4; that it is largely untreated; and that it is associated with the early development of hyperparathyroidism,” investigators concluded.

The largest survey of hemodialysis patients recently carried out in Canada showed that K/DOQI target rates are increasingly being reached, with over 60% of 2337 hemodialysis patients achieving serum phosphorus control.

Whether more widespread uptake of newer phosphate binders, including lanthanum carbonate, will improve phosphorus control rates has yet to be evaluated in Canada, but a prospective observational study in 45,562 hemodialysis patients from a large US organization suggests that sustained use of lanthanum carbonate appeared to have a favourable effect on both serum and calcium phosphorus levels. Mean baseline calcium (taken closest to starting lanthanum carbonate) for the group was 9.6 mg/dL; mean phosphorus was 6.9 mg/dL; mean calcium phosphorus product was 66 m2/dL; and the mean intact PTH was 540 pg/mL. The mean dose of lanthanum carbonate for those who remained on lanthanum carbonate for at least four quarters was 2.5 g/day.

After its introduction in late 2004, lead investigator Wendy St. Peter, PharmD, US Renal Data System and Associate Professor, University of Minnesota, Minneapolis, and colleagues found that almost 15% of hemodialysis patients were taking lanthanum carbonate by April 2006. The group also found that of 2190 patients followed through to April 2006, 42% had achieved a K/DOQI target for corrected calcium compared with 38% of those on prior binder therapy.

This was also true for 30% of patients on lanthanum carbonate who achieved K/DOQI phosphorus targets vs. 19% at baseline, while 39% of patients on lanthanum carbonate achieved the K/DOQI calcium phosphorus product target vs. 26% on prior binder therapy.

Summary

Achieving K/DOQI targets for mineral abnormalities remains challenging and few CKD patients achieve all three targets for calcium phosphorus, serum phosphorus and PTH. Nevertheless, the 750 mg and 1 g formulations of lanthanum carbonate significantly reduce pill burden compared with other phosphate binder regimens and should help address difficulties with compliance. Whether greater use of these formulations will improve overall phosphate control is not yet known, but its advantage may be that it will allow more patients to reach K/DOQI targets with a single tablet per meal, thereby simplifying complex treatment regimens and potentially improving quality of life for CKD patients.

Questions and Answers

This question-and-answer section was conducted with Monique Elseviers, PhD, Department of Nursing Sciences, University of Antwerp, Belgium, and Dr. David Mendelssohn, Associate Professor of Medicine, University of Toronto, Ontario, during the scientific sessions.

Q: Approximately 30% of patients could not fully comply with their phosphate binder regimen over a period of 15 weeks and even among those who did, serum phosphorus levels were often too high. What are your recommendations in such a situation?

Dr. Elseviers: More and more I believe you need to take an individual approach to each patient’s problems with compliance because for each patient, the reason they aren’t taking their pills may be different. For example, some patients do not fully understand the repercussions of the treatment, and become less compliant. In some patients whose disease is at an advanced stage and have a higher rate of comorbidities, they might also be less compliant. Therefore, many aspects that are included into non-compliance can be improved but it takes an individual patient approach.

Q: Do you believe that having a large dose of phosphate binder in a single tablet formulation might help more patients achieve K/DOQI phosphate targets?

Dr. Mendelssohn: In theory, yes, the biggest advantage of lanthanum carbonate is that the 1g tablet is all you need. So 1 g per meal works for most patients so if patients are more compliant with lanthanum carbonate, then it is quite possible that phosphorus control will be better.