Effects of the Use of Non-Calcium Phosphate Binders in the Control and Outcome of Vascular Calcifications
Effects of the Use of Non-Calcium Phosphate Binders in the Control and Outcome of Vascular Calcifications: A Review of Clinical Trials on CKD PatientsPiergiorgio Bolasco, Italy
International Journal of Nephrology Volume 2011, Article ID 758450
Vascular calcifications produce a high impact on morbidity and mortality rates in patients affected by chronic kidney disease and mineral bone disorder (CKD-MBD). Effects are manifested from the more advanced stages of CKD (stages 3-4), particularly in patients undergoing dialysis (CKD5D). In recent years, a large number of therapeutic options have been successfully used in the treatment of secondary hyperparathyroidism (SHPT), despite eliciting less marked effects on nonbone calcifications associated with CKD-MBD. In addition to the use of Vitamin D and analogues, more recently treatment with calcimimetic drugs has also been undertaken. The present paper aims to analyze comparative and efficacy studies undertaken to assess particularly the impact on morbidity and mortality rates of non-calcium phosphate binders. Moreover, the mechanism of action underlying the depositing of calcium and phosphate along blood vessel walls, irrespective of the specific contribution provided in reducing the typical phosphate levels observed in CKD largely at more advanced stages of the disease, will be investigated. The aim of this paper therefore is to evaluate which phosphate binders are characterised by the above action and the mechanisms through which these are manifested.
Over the last 10 years, it has become increasingly apparent that chronic kidney disease-mineral and bone disorder (CKD-MBD) is associated to extra-skeletal manifestations, particularly cardiovascular calcifications in patients at the more advanced stages of CKD. The following manifestations have been observed: calcifications of the aorta, the carotid and the coronary arteries resulting in a reduced elasticity, diameter, compliance, and distensibility. The disease is not confined to central blood vessels but also involves the iliac-femoral axis and all arteries in the limbs, thus producing a high impact on the quality of life, morbidity and mortality of these patients . An additional element implicated in the morbidity and mortality of patients is represented by the manifestation of calcifications on the endothelium of heart valves, in particular the mitral and aortic valves. A fundamental impetus in the study of compression exerted by calcium deposits in the vessels was provided by Raggi using highly advanced procedures such as electron-beam computed tomography (EBCT), partic- ularly to assess the involvement of coronary arteries. Hyperphosphatemia is one of the main features of chronic kidney disease-mineral and bone disorder (CKD-MBD). An excess of phosphorus represents an independent risk factor for cardiovascular morbidity and mortality in patients with advanced CKD. Options available for use in the treatment of hyperphosphatemia are severe control of dietary phosphorus intake, use of phosphate binders, and optimized phosphorus output choosing high-efficiency dialysis as high flux-methodology. Phosphate binders are used for their binding actions to reduce the absorption of phosphorus by the gastrointestinal lumen.
Calcium phosphate binders such as calcium carbonate or acetate are still widely used today. Evidence of an increased risk of onset and progression of nonbone, particularly vascular, calcifications has led to the use of caution by nephrologists, in spite of the markedly lower costs compared to the price of the new non-calcium. The concept whereby the at times excessive use of calcium-containing phosphate binders would appear to be widely accepted, together with the notion that in the future patients at the CKD5D stage should be treated to return dialysate calcium concentration to values below 1.5 mmol/L. The latter is particularly important in patients undergoing peritoneal dialysis who are exposed at length to transfers of mass and therefore a long- lasting, harmful positive calcium balance.
The aim of the present review is not to illustrate the specific actions produced by calcium-based binders and other drugs, including calcimimetic agents, but rather to focus on the direct and indirect mechanism of action of non- calcium phosphate binders. In doing so, emphasis will be placed almost exclusively to recent studies undertaken and no reference was made to morbidity and mortality rates, which are beyond the scope of this paper.
Methods Applied in Literature Review
Two hundred and thirty-seven published papers describing a correlation between hyperphosphatemia in CKD and vascular calcifications were analyzed. Subsequently, papers relating to a total of 9 randomized trials or featuring an effective study design were selected. All studies had focused on the use of non-calcium phosphate binders as a therapeutic option aimed at reducing nonbone, and prevalently vascular, calcifications in a population of 879 patients. The trials taken into consideration are listed in Tables 1 and 2.
Mechanisms of Action
The mechanism through which non-calcium phosphate binders exert their action and slow down progression of vascular calcifications is still unclear and remains to be clarified. However, the RIND study, evaluating progression of coronary artery calcification in incident hemodialysis patients, demonstrated that vascular calcification processes manifest in predialysis stages in the majority of patients, which may well be linked to deranged calcium and phosphate homeostasis. Novel insights into the pathophysiology of calcium and phosphate handling, especially the discovery of the phosphatonin FGF23, suggest that a more complex assessment of phosphate balance is warranted. This assess- ment should include measurements of fractional phosphate excretion and phosphatonin levels to objectively judge and effectively correct phosphate overload .
New markers, such as FGF-23, have been identified as inducers of vascular calcification and cardiovascular disease in CKD. Therefore, the use of calcium-free phosphate binders may reduce the risk of cardiovascular disease by reducing both serum phosphate and FGF-23 levels . Recent findings have provided evidence of a direct action of non-calcium phosphate binders on the progression of vascular calcifications. Data published to date on the use of non-calcium phosphate binders such as sevelamer and lanthanum carbonate recommend the administration of these drugs from the initial stages of CKD in association with a dietary intake of phosphorous in order to prevent an increase in FGF-23 and the action produced by the later on vascular calcifications [39, 40].
To conclude, a large number of reports present in literature recommend that serum phosphate levels be closely monitored, whilst at the same time not overlooking important aspects such as eliciting a decrease in the onset and progression of vascular calcifications that produce a marked effect on the morbidity and mortality rates of CKD patients at all stages. The tendency is to reduce calcium intake both through dialysis and by administration of non-calcium phosphate binders that have proved effective in controlling hyperphosphatemia but which also feature pharmacological characteristics capable of producing a direct decrease in calcifications to the vascular endothelium. In spite of the large body of evidence provided in literature, further ran- domized, prospective studies should be undertaken with the specific aim of evaluating the incident population to provide further confirmation and optimization of the beneficial effects reported to date.