Hyperphosphatemia and phosphate binders: effectiveness and safety

Abstract

In patients with kidney dysfunction hyperphosphatemia is more evident as renal failure progresses. It is related to increased FGF-23 levels, secondary hyperparathyroidism, and accelerated progressive vascular calcification. In CKD patients advanced coronary artery calcification is strongly associated with future cardiovascular events, cardiovascular death, and all-cause mortality. Apart from the above, phosphate per se is suspected as a causal risk factor for CKD progression. Keeping serum phosphorus within the target values are linked to improvement in life expectancy. A low phosphate diet, an efficient dialysis removal of phosphate load, and the administration of phosphate binders are the main recommended steps to control hyperphosphatemia. Calcium-based phosphate binders can lead to a positive calcium balance, hypercalcaemia, parathyroid gland suppression, adynamic bone disease, and coronary artery and aortic calcification. On the other hand Sevelamer hydrochloride and Lanthanum carbonate has been shown to be effective, safe and useful therapeutic tools for hyperphosphatemia. When prescribe pharmacological agents, one must take into account the large increase in health-care expenditure and the choice of phosphate binder should be individualized.

Keywords::

• Effectiveness
• Hyperphosphatemia
• Phosphate binders
• Safety

Hyperphosphatemia in patients with end-stage renal disease

Phosphorus is a critical element in numerous physiologic functions such as skeletal development, mineral metabolism, cell membrane phospholipid function, mitochondrial metabolism, cell signaling, and platelet aggregation1. As a total adult body stores is approximately 700 g, of which 85% is contained in bone, 14% is intracellular, and only 1% is extracellular. Of extracellular phosphorus, 70% is organic and contained within phospholipids, and 30% is inorganic, of which 15% is protein bound, and the remaining 85% circulates as the free mono- or di-hydrogen forms or it is complexed with calcium sodium or magnesium. Only this latter 15% of extracellular phosphorus is freely circulated and measured1.

A typical diet ingests approximately 1000–1400 mg phosphorus per day. About 2/3 of the ingested phosphorus is excreted in the urine, and the remaining 1/3 in stools. This phosphorus excretion is highly dependent on kidney function and obviously chronic renal failure is by far the most frequent cause of hyperphosphatemia.

Phosphate retention begins in early renal failure, due to the reduction in the filtered phosphate load. Hyperphosphatemia is evident as renal failure progresses into late stages.

Secondary hyperparathyroidism, vascular calcification and cardiovascular risk

In the general population, coronary artery calcification is an important prognostic factor associated with future cardiovascular events. Hyperphosphatemia is related to accelerate progressive vascular calcification, which might play a role in the development of this disorder2. The pathophysiology of vascular calcification involves the conversion of vascular smooth muscle cells into bone forming, osteoblast-like, cells. In this regard, high concentrations of serum calcium and phosphorus are among the factors that promote this change in cell types3.

In end-stage renal disease (ESRD) patients on hemodialysis (HD), advanced coronary artery calcification was strongly associated with future cardiovascular events, cardiovascular death, and all-cause mortality. Furthermore, in new HD subjects baseline coronary artery calcification score was a significant predictor of all-cause mortality4,5.

A possible pathophysiological mechanism is potentially mediated by the phosphaturic hormone fibroblast growth factor-23 (FGF-23). The development of renal failure induces phosphate retention and leads to hypersecretion of FGF-23. The increase in FGF-23 results in increased urinary phosphate excretion and suppression of 1,25(OH)2D. Parathormone (PTH) increases in response to reductions in 1,25(OH)2D. As a consequence, hyperphosphatemia is related to increased FGF-23 levels, secondary hyperparathyroidism, vascular calcification and the development of cardiovascular disease6–8.

The control of hyperphosphatemia: oral phosphate-binding drugs

Phosphate per se is increasingly suspected as a causal risk factor for CKD progression shown in experimental models9 and in observational studies with CKD patients10. Proteinuria entails a high risk of progression towards kidney failure. However, in proteinuric CKD patients high levels of phosphate attenuated the nephroprotective effect of renin–angiotensin system inhibitors11. Furthermore, recent observations in the general population without evidence of CKD also associate relatively higher serum phosphate levels with albuminuria12.

In patients with kidney problems, the rationale for controlling serum phosphorus and the recommended goals of therapy must therefore be based on the aforementioned observational and epidemiological evidence. Keeping serum phosphorus and calcium levels simultaneously within the management target values is linked to improvement in life expectancy13.

The first step to point out is the importance of lowering intestinal phosphate absorption with a low phosphate diet. Interestingly, recent evidence suggests that it would be better to lower the amount of phosphate in the diet rather than rely on pharmacological interventions14. However, dietary restriction of phosphorus prompts the question whether it is sufficient to control serum phosphate levels, while maintaining adequate protein intake. In HD patients, the second step is to ensure an efficient dialysis removal of phosphate load. The third step is foods or medications that bind with phosphorus, such as antacids, phosphate binders, or calcium, which can decrease the free phosphate for absorption. In the majority of patients with hyperphosphatemia the prescription of a phosphate binder is required. This raises the question of which type of phosphate binder should be prescribed in these patients.

The first phosphate binders used were aluminum-containing agents, which are highly effective at binding phosphate. However, in an epidemiological survey of dialysis units, concentration of aluminum in dialysate water correlated with the incidence of both aluminum bone disease and encephalopathy15. Because of their toxicity these agents are no longer used.

The most widely used phosphate-binding drugs were calcium based salts. It should be acknowledged that modest doses (approximately 1 g of elemental calcium) may represent a reasonable initial approach to reduced serum phosphorus levels. On the other hand, in patients on HD, a factor leading to the progression of vascular calcification is calcium overload. It has been shown that calcium-based phosphate binders can lead to a positive calcium balance and are correlated more closely with hypercalcemia, parathyroid gland suppression and adynamic bone disease, especially when mineral metabolism is not well controlled. In HD patients, calcium adversely influences the balance of skeletal and extra-osseous calcification16 and is associated with progressive coronary artery and aortic calcification. Progression of coronary artery calcification has been associated with an increase in vascular stiffness and QT dispersion regarded as a marker of increased risk of ventricular arrhythmias17. Delaying progression or promoting regression of vascular calcification may therefore improve survival among patients on HD5 and it is clear from the foregoing discussion that when large doses of binder are required a non-calcium-based binder can then be added.

Sevelamer hydrochloride is a non-absorbable high-molecular-weight compound effective in reduced phosphorus. It is the only non-calcium-containing phosphate binder that does not have potential for systemic accumulation. The agent has been found to delay the progression of coronary artery and aortic calcification, exhibits pleiotropic effects that may affect the development of cardiovascular disease and was associated with a significant survival benefit compared to the use of calcium-containing phosphate binders5,6. Additionally, in CKD patients it affects inflammatory biomarkers such as C-reactive protein and can improve lipid profile18. A post hoc evaluation of the CALcium acetate MAGnesium carbonate (CALMAG) study clearly showed that sevelamer and the combination of calcium acetate and magnesium carbonate (CAMC) comparably lower serum levels of FGF-23. However, in contrast with sevelamer, the combination of CAMC had no influence on bone turnover markers19. However, in stage 3 non-diabetic CKD patients, sevelamer does not provide evidence of improvement in left ventricular mass, left ventricular function, or arterial stiffness14.

Lanthanum carbonate is a non-calcium-based phosphate binder, which contains the rare earth element lanthanum. It is absorbed in the gut and has a biliary route of excretion. In controlled clinical trials, it has been shown to be effective and well tolerated in patients with CKD. It is useful as a therapeutic tool for hyperphosphatemia for short- or long-term treatments and showed significant dose-related reductions in serum phosphorus20.

In this issue, the new systematic review and meta-analysis of 960 patients in seven placebo randomized controlled trials by Huang et al.21 confirmed that lanthanum as a non-calcium-containing phosphate binder is well tolerated, and could effectively control hyperphosphatemia during short-term trials. According to the study, patients treated with lanthanum showed less change in serum PTH as well as calcium and phosphorus product from baseline, compared to placebo group. This is coupled with a previous meta-analysis that compared the effects of non-calcium phosphate binders with calcium-based agents on biochemical markers and clinical end-points. In that analysis, lanthanum significantly decreases the end-of-treatment serum calcium and calcium-phosphorus product levels, with similar end-of-treatment phosphorus levels22. Despite the trends observed, the study did not find a statistically significant difference in cardiovascular mortality and coronary artery calcification in patients receiving calcium-based phosphate binders compared to non-calcium-based phosphate binders4. Another recent meta-analysis, including 11 randomized trials with 4622 patients, aimed to provide the best available evidence as to which type of phosphate binder clinicians should prescribe to patients with CKD. It showed that patients assigned to non-calcium-based binders exhibited a 22% reduction in all-cause mortality compared with those assigned to calcium-based phosphate binders23. The reduction in vascular calcification was greater in patients assigned to non-calcium-based binders than in those assigned to calcium binders at all time points. The potential explanation for the mortality decrease associated with the use of non-calcium-based binders might be related to slowing vascular calcification. This is also supported by additional evidence which suggest that switching phosphate binder from calcium carbonate to lanthanum carbonate delayed the progression of calcium calcification in patients on HD24.

Safety and tolerability considerations

The synthetic polymer sevelamer hydrochloride is a non-aluminum- and non-calcium-containing phosphorus binder, but various factors need to be taken into account with it, mainly low compliance with drug regimens because of gastrointestinal side-effects, such as constipation25.

Lanthanum carbonate, which is a non-aluminum- and non-calcium-containing phosphorus binder, has confirmed long-term safety24,25. Its main excretion route is through the bile, and it is thought to be advantageous for patients with renal insufficiency. The systematic review and meta-analysis in this issue21 confirmed that the incidence of drug-related adverse events was similar between placebo and lanthanum treated patients.

It is important to bear in mind the large increase in health-care expenditure when prescribing pharmacological agents and we must recognize that all non-calcium-containing phosphate binders are much more expensive than calcium based salts. Of note, all the current data does not support the comparative superiority of non-calcium binding agents over calcium salts and there is no convincing evidence that lowering serum phosphorus to a specific target range leads to improved clinical outcomes in patients with CKD. On the other hand, in patients treated with a calcium containing binder, the frequency of hypercalcemia also increases the possibility of precipitating ectopic calcification. As a result, it seems more logical that the choice of phosphate binder should be individualized. Various factors need to be accounted for when considering the choice of phosphate binder, such as the cost of the drug, the patient’s tolerability and any comorbidity, as well as the effects on mineral metabolism. Clearly, further research is needed to unequivocally show the beneficial effects of phosphate binders on cardiovascular risk and mortality.

Transparency

Declaration of financial/other relationships

R.G.K. and M.S.E. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article.