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 2008 Spring Clinical Meetings

Dallas, Texas / April 2-6, 2008

In healthy individuals, phosphate remains in a state of perfect homeostasis, as the amount consumed or secreted endogenously is counterbalanced by normal metabolism, absorption, and excretion. In patients with chronic kidney disease (CKD), a phosphorus imbalance often occurs, stated Dr. Stuart M. Sprague, Professor of Medicine, Northwestern University, Chicago, Illinois. The body’s ability to process metabolism declines as the disease progresses, resulting in excess serum phosphate.

“That excess phosphorus has to go somewhere, and it often is absorbed into soft tissues, including tissues of the cardiovascular system,” he explained. “Absorption of phosphorus into cardiovascular tissues raises levels of intracellular calcium and eventually can lead to vascular calcification.”

Higher phosphate levels, even within the normal range, have implications for clinical events, Dr. Sprague continued. For example, an analysis of the association between serum phosphorus clinical events in patients with coronary artery disease showed that mortality and the risk of myocardial infarction (MI) and heart failure all increased with serum phosphate levels (Tonelli et al. Circulation 2005;112:2627-33).

Enhanced recognition of the threat posed by rising serum phosphate has focused attention on strategies to reduce phosphorus levels. The principle of dietary control has widespread acceptance, but its precise role remains a matter of debate.

Dietary Control

In its guidelines for managing parathyroid hormone (PTH) levels in patients with CKD, the National Kidney Foundation recommends dietary restriction of phosphorus should be implemented whenever serum phosphorus levels are elevated in stage 3-4 CKD (Am J Kidney Dis 2003;42 [4 suppl 3]:S1-S201) (Table 1). A common definition of elevated phosphorus is serum levels >4.6 mg/dL, noted Dr. Daniel Coyne, Professor, Department of Internal Medicine, Washington University, St. Louis, Missouri.

Putting evidence and recommendations into perspective, Dr. Coyne acknowledged that multiple studies have demonstrated an association between higher phosphate levels and an increased risk for morbidity and mortality. However, scientists have yet to make the leap to causality.

Table 1. Dietary Phosphorus Restriction for Control of PTH in CKD

“Association does not necessarily mean causation,” cautioned Dr. Coyne. “Just because people who live longer have a lower phosphorus doesn’t mean that making the phosphorus lower will make people live longer.”

That point seemingly was demonstrated in the Modification of Diet in Renal Disease (MDRD) study from the 1990s. The results showed that dietary control did not halt progression of CKD (Kopple et al. Kidney Int 1997;52:778-91). However, the study had a number of problems, remarked Dr. Coyne, including short duration, lack of a control group, inclusion of a heterogeneous population that included nonadherent and nonprogressing patients, and unregulated use of ACE inhibitors. With longer follow-up in the MDRD, a trend toward a reduced risk of progressive disease emerged in patients who had moderate CKD at enrolment (Levey et al. Am J Kidney Dis 2006;48:879-88).

Although dietary restriction has a mixed record in CKD and hyperphosphatemia, binding agents also have not achieved consistently favourable results, Dr. Coyne continued. For example, a recent placebo-controlled study of calcium supplementation in healthy postmenopausal women revealed a doubling of the risk of MI in the group that received calcium. The incidence of stroke and the composite end point of MI, stroke, and sudden death trended toward an increased hazard with calcium supplementation (Bolling et al. BMJ 2008; 336:262-6).

Summarizing the volume of data, Dr. Coyne noted that dietary restriction addresses numerous metabolic issues in patients with CKD and should remain a cornerstone of comprehensive CKD care. Restricting dietary protein to 0.8 to 1.0 g/kg/day may slow renal failure and has the advantage of safety.

Dr. Coyne cautioned listeners, “Conventional phosphorus binders have not been proven to be safe or to slow renal failure in CKD, and that use of phosphorus binders may mislead patients and physicians into believing that dietary restrictions are not important.”

Responding to Dr. Coyne’s comments, Dr. Kamyar Kalantar-Zadeh, Associate Clinical Professor of Medicine, Harbor-UCLA Medical Center, Torrance, California, returned the focus to data showing that rising serum phosphorus levels are associated with an increased mortality risk (Kalantar-Zadeh et al. Kidney Int 2006; 70:771-80) (Figure 1).

Figure 1. Ris
y Varying Phosphorus

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“Controlling serum phosphorus is an important goal in the management of renal osteodystrophy in CKD,” he stated. “The two main phosphorus-control strategies are administration of phosphate binders and adherence to a low-phosphorus diet. Low-phosphorus diets are usually associated with low protein intake, which can lead to poor outcome.”

Moreover, determining dietary phosphorus intake has been complicated by the increasing proportion of phosphorus that comes from inorganic sources, he continued. Dr. Kalantar-Zadeh also stated that the notion that protein intake determines serum phosphorus levels is outdated. He cited findings from a study of associations between dietary protein intake and survival in hemodialysis patients (Shinaberger et al. Am J Kidney Dis 2006;48:37-49). Using normalized protein nitrogen appearance (nPNA) as a reflection of protein intake, investigators found that the best survival was associated with the combination of increased nPNA and decreased phosphorus levels. The worst survival occurred in patients who had low daily protein intake (as assessed by nPNA) or a decrease in protein intake over time plus a decrease in serum phosphorus.

A Third Option

The phosphorus debate involves a third option that addresses some of the limitations and criticisms associated with dietary restriction and conventional phosphorus binders. Lanthanum carbonate is a non-calcium, non-resin phosphate binder that has demonstrated efficacy in reducing serum phosphate levels in patients with stage 5 CKD requiring dialysis (Hutchison et al. Nephron Clin Pract 2006;102:61-71).

Evidence of vascular calcification often emerges early in the course of CKD, raising the possibility that patients with stage 3-4 disease might benefit from phosphate-binder therapy. Dr. Sprague and colleagues reported findings from the SPD405-205 study, a randomized, multicentre, placebo-controlled clinical trial to evaluate the efficacy and safety of lanthanum carbonate in patients with stages 3-4
gure 2. SPD405-206 Study: Change from Baseline in Serum Phosphorus

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The study involved 121 patients with an estimated glomerular filtration rate of 15 to 59 mL/min/1.732 and serum phosphorus levels >4.6 mg/dL. The patients were randomized 2:1 to lanthanum carbonate 750 mg/day, administered as a single table three times daily during or immediately after meals for two weeks, or to matching placebo. The starting dose was titrated to a maximum of 3000 mg/day during weeks 3 to 4 to achieve a target serum phosphorus level <4.0 mg/dL. The final titrated dose was continued for an additional four weeks.

The primary end point was the percentage of patients with serum phosphorus <4.6 mg/dL after eight weeks of treatment. A total of 71 patients completed the study. At the end of the study, 44.6% of patients in the active treatment group had serum phosphate concentrations £4.6 mg/dL compared with 26.5% in the placebo group (P=0.12).

Patients on active treatment had a significantly greater reduction in mean serum phosphorus from baseline (P=0.02). At the end of the study, urinary phosphorus excretion had decreased by 247.7 mg/day in this group vs. <100 mg/day in the placebo group (P=0.04). Serum intact parathyroid hormone (PTH) levels decreased by 23.8 pg/mL with lanthanum carbonate and increased by 8.8 pg/mL in the placebo group (P=0.02).

Dr. Sprague and colleagues reported that 47.4% of patients in the active treatment group had adverse events compared with 61% in the placebo group. The most commonly reported adverse events were nausea and vomiting, which occurred in <10% of patients in each group. Examination of the adverse events indicated that 19.3% of events in the lanthanum carbonate group were drug-related as were 16.7% of events in the placebo group.

“Our study, along with others, suggests that serum phosphorus is a late and insensitive marker for phosphorus burden in CKD patients not requiring dialysis,” the authors concluded. “In such patients, serum phosphorus concentrations should not be considered in isolation but with other markers of disordered mineral metabolism; for example, urinary phosphorus excretion, calcium x phosphorous product, and PTH.”

Managing Calciphylaxis: A Case Report

A case report presented at the NKF meeting suggested lanthanum carbonate might have a role in the treatment of calciphylaxis, or calcific uremic arteriolopathy, a rare and debilitating vasculopathy occurring predominantly in patients with renal failure or other risk factors (Couto et al. Endocr Prac 2006;12:406-10). Though the etiology remains unclear, the proposed mechanism of injury is active vascular calcification associated with elevated PTH.

The patient was a 64-year-old man with a history of cryptogenic cirrhosis. On admission, he had worsening liver failure, hypotension, and renal failure, reported Dr. Micah Chan, Section of Nephrology, University of Wisconsin, Madison, and colleagues. Laboratory results showed a BUN of 106 mg/dL (37.8 mmol/L), creatinine 3.1 mg/dL (274.0 mmol/L), total calcium 6.7 mg/dL (1.67 mmol/L), phosphorus 4.8 mg/dL (1.55 mmol/L), calcium x phosphorous product 32.2 mg2/dL2 (2.58 mmol2 /L2 ), and al
g/L). Blood, urine, and peritoneal fluid cultures were negative (Table 2).

Table 2. Calciphylaxis: Case Study

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On day 20, the patient’s calcium level had risen to 10 mg/dL and serum phosphate to 7.1 mg/dL. The calcium x phosphorous product was 73.1 mg2/dL2. Low calcium dialysate was initiated, and dialysis time was increased. However, the patient’s calcium x phosphorous product continued to rise, reaching a maximum of 135.7 mg2/dL2. PTH was normal at 20 pg/mL.

Calcium-based phosphate binders could not be used because of the patient’s elevated calcium, and sevelamer hydrochloride was not given because of difficulties related to administration. The patient was started on lanthanum carbonate 1000 mg t.i.d. and continued dialysis.

Over the next eight weeks, the patient’s calcium and phosphorus levels improved to a more manageable state, associated with a product average of 35.5 mg2/dL2. His nutrition status also improved, reflected in a serum albumin of 3.8 g/dL, and intact PTH remained in the normal range.

Dr. Chan and colleagues concluded, “Lanthanum may be an effective therapy for calciphylaxis in combination with modified hemodialysis. The rapid response to treatment may hold promise for many patients suffering from this deadly and debilitating syndrome.”

Summary

CKD causes multiple metabolic disturbances, including elevations in serum phosphorus. Studies have shown an increased mortality risk associated with rising serum phosphorus, even within the normal range. The role of dietary restriction in the management of serum phosphate remains open to debate. Calcium-based phosphate binders can exacerbate already-elevated calcium levels and add substantially to a patient’s pill burden. The non-calcium phosphate binder lanthanum carbonate has demonstrated potential in managing serum phosphate levels safely and effectively with dosing.