1 Duke Institute of Renal Outcomes Research and Health Policy, Duke University Medical Center, Durham, NC and 2 Downstate Medical Center, Brooklyn, NY, USA
Keywords: calcium-containing phosphate binders; end-stage renal disease; vascular calcification
Recently, there has been intense interest in vascular calcification and the use of calcium-containing phosphate binders for patients with end-stage renal disease (ESRD). A multi-centre trial evaluating the role of calcium-containing phosphate binders vs non-calcium, non-aluminum-containing binders and the progression of coronary calcification by electron beam computerized tomography (EBCT) has been underway for approximately 1 year. The interim results support observational data that the administration of calcium salts is associated with progressive coronary calcification, in contrast to non-calcium containing binders [1].
Vascular calcification occurs at two pathologic sites: in the intima, where it is invariably associated with atherosclerosis, and in the tunica media, where it is relevant to loss of vascular elasticity and compliance [2]. Medial calcification, also known as Mönckeberg's sclerosis, is common and so may occur independently of atherosclerosis, thus implying different aetiological mechanisms from intimal calcification [2]. It has been posited that accelerated vascular calcification of the intima is provoked in ESRD patients by the putative systemic calcium load arising from the use of calcium-containing phosphate binders, and thus contributes to patients' increased cardiovascular morbidity and mortality. While there is some clinical evidence to support this contention, these associations are circumstantial and fraught with considerable confounding on critical examination.
Coronary artery calcification may be a highly reliable predictor of atherosclerotic coronary artery disease among the general population [3,4] and can be measured by non-invasive techniques such as conventional computed tomography [57], spiral computed tomography [8], ultra-fast, EBCT [912], and fluoroscopy [1318]. ESRD patients have an exaggerated risk of cardiac events and mortality [1925], and some patients are observed to have a 2.55-fold increase in coronary artery calcium scores compared with non-dialysis patients [26]. For example, in a relatively small, observational cohort study, it was reported that coronary artery calcification was common and progressive among young ESRD patients [27]. In this cohort, increased coronary artery calcification was directly associated with reported oral calcium intake; patients with progressive calcifications were prescribed almost 2-fold greater amounts of calcium in phosphate binders compared with patients with calcium scores within the normal range. Interestingly, parathyroid hormone (PTH) levels did not correlate with coronary calcifications. Similarly, in another small observational study, it was observed that carotid artery compliance and vascular calcifications were positively associated with reported calcium ingestion among ESRD patients [28]. PTH levels, however, were negatively correlated with calcium scores. Based on these studies, and an unproven chain of logic, calcium salts have been incriminated as provocateurs for vascular calcification. Moreover, some clinical thought leaders have advocated for the virtual abandonment of calcium-containing phosphate binders in exchange for newer, more costly, non-calcium, non-aluminum, non-magnesium containing agents.
Although the pathobiologic chain of logic appears sound, we urge that the renal community be circumspect of the putative, isolated role of calcium salts in the pathobiology of coronary artery calcification. Several troubling issues impugn the interpretation of the associations, such as: (i) a flawed causal pathway linking calcium ingestion to intimal calcifications; (ii) the occurrence of coronary artery calcifications in patients not exposed to calcium salts as phosphate binders; (iii) the absence of uniformity of the associations between changes in divalent ion concentrations, PTH level, and extent of intimal calcifications; (iv) limitations of study design in those cases in which an association with reported calcium intake is reported; and (v) the assumption that coronary artery calcification is a suitable surrogate outcome for clinically relevant atherosclerotic cardiovascular disease. We will examine each of these issues.
First, calcium-containing phosphate binders are purported to be a dietary source of excessive amounts of the elemental calcium contributing to the development and progression of coronary artery calcification. This physiologic scenario is plausible if calcium-containing salts are ingested in excess or incorrectly timed with meals. The pathobiologic model predicts that the serum calcium concentration will be positively associated with coronary calcification in ESRD patients. However, when ingested properly, calcium salts dissociate and form a relatively insoluble complex with dietary phosphorus in the gastrointestinal tract [29,30]. The calcium is thereby sequestered, so that substantial amounts are unavailable for absorption. We suggest that if systemic hypercalcaemia is a major provocateur for arterial calcification, an alternative exogenous source of calcium should be considered, such as the dialysate. Current data suggests that dialysis patients with normal pre-dialysis serum calcium concentrations are in negative calcium balance with a 1.25 mmol/l dialysate calcium concentration and in balance when treated with 1.5 mmol/l dialysate calcium concentration, respectively [31]. Therefore, it is likely that positive calcium balances develops when patients are routinely exposed to the more conventional dialysate calcium concentrations of 2 mmol/l. Thus, if a pathobiologic link exists between calcium loads and arterial calcification in standard contemporary clinical practice, the dialysate should be scrutinized, as well. It is noteworthy that the serum calcium concentration does not correlate with death risk, nor are serum calcium concentrations elevated in studies quantifying coronary calcification in ESRD patients [26,27,32].
An alternative mechanism(s) for accelerating coronary artery calcification, unrelated to calcium-containing phosphate binders is suggested by the observation that patients with more coronary calcification had reduced skeletal mass [26]. It is suggested that the pathobiology may involve calcium mobilization from bone, rather than external loading, or that bone buffering of a calcium load may be limiting. The skeletal system has extensive buffering capacity for serum calcium levels, which may be attenuated, during states of low-bone turnover [33]. An increased exogenous calcium load may contribute to increased vascular calcification in the setting of such low-bone turnover states. It is noteworthy that adynamic bone disease is common in surveys of bone pathology among ESRD patients and that patients with this abnormality were found to have abnormal calcium homeostasis [34] and higher morbidity and mortality rates than patients exhibiting other histological abnormalities [35].
Other processes associated with ESRD may account for accelerated atherosclerotic calcification and define its extent. Alternative and more likely provocateurs include other prevalent and severe atherogenic abnormalities in ESRD, such as oxidative damage to the endothelium, quantitative and qualitative abnormalities of lipoproteins, and/or hyperhomocysteinaemia [36]. This is further supported by the fact that intimal calcification occurs exclusively in atherosclerotic arteries present soon after fatty streak formation [37] and is absent in normal vessel wall [38,39].
Limiting the interpretation of the relationship between atherosclerotic plaque calcification and clinical outcomes is the uncertainty of its prognostic meaning. For example, some studies suggest that plaque calcification may be protective, despite its statistical association with increased morbidity [40]. This hypothesis has been supported by studies of human atherosclerotic plaques which have revealed that calcification does not decrease the mechanical stability of the coronary atheroma as does lipid inclusion [41]. Moreover, there was an inverse relationship between the per cent area of calcification and maximum principal stress. Alternatively, there was a significant positive correlation between stress and per cent area of lipid. These findings are consistent with the success of lipid-lowering therapies in the prevention of coronary events [42] and may challenge the utility of therapies targeted against calcified lesions as opposed to those treating the systemic manifestations of atherosclerosis, specifically inflammation, intimal injury, and dyslipidaemia.
In view of the atherogenic milieu associated with ESRD, it is unsurprising that cardiac calcifications and an excessive cardiovascular mortality were observed in dialysis patients decades before the prevalent use of calcium-containing phosphate binders [43]. Many of these historic patients received aluminum-based phosphate binders and had hyperphosphataemia and secondary hyperparathyroidism with hypocalcaemia [4345]. Therefore, it is predictable that the degree of coronary artery calcification does not correlate with serum calcium, phosphorus, or PTH levels in a recent study [27]. In contrast, several data sets have demonstrated a significant increase in mortality risk associated with elevated serum phosphate concentrations, especially for values >6.5 mg/dl and [calcium]x[phosphate] >72 mg2/dl2 [32,46]. The inconstancy of the statistical associations between divalent ions and coronary calcifications may be affected by differences among patient cohorts across studies, associations due to co-linearity in disease processes rather than causality, and/or limitations of study designs.
This fourth issue of study design limitations substantially compromises putative pathobiologic links to calcium-containing phosphate binders. The preponderance of studies examining the relationship between calcium-containing phosphate binders and coronary artery calcifications are cross-sectional and observational. Although hypothesis generating based on the security of the described statistical associations, the burden of proof for causality is not met by this analytic design. In addition, because of their uniform small size, they may not be adequately powered to detect other possible relationships in the pathobiology of coronary artery calcification and to exclude statistical confounders. For example, reported calcium intake may be a surrogate for the severity of hyperparathyroidism. Because the latter is a time-dependent, continuous measure, whose risk may be non-linear and persist even after levels have been normalized, small cross-sectional or short longitudinal trials may not be adequately powered.
A particularly troubling limitation of these previous analyses is their uniform reliance on reported or prescribed calcium intake, rather than measured amounts. Repeated voluntary non-adherence with ingestion of calcium-containing phosphate binders has been reported in 6580% of dialysis patients [47]. Let us assume that many patients in a trial overstate their compliance with their calcium-containing phosphate binder. Because a benchmark reduction in the serum phosphorus concentration is not achieved, the prescribed dose of calcium salt is increased. Using a similar chain of logic, such patients may have accelerated calcification related to poor phosphorus control and/or its consequences. However, an analysis that fails to account for a disparity between the prescribed and the ingested dose of calcium may detect a misleading statistical association with higher doses of calcium.
A final concern is the uncertainty about the clinical consequences of coronary calcifications among patients with ESRD. EBCT has a high sensitivity for detecting the presence of calcified coronary artery lesions. However, its specificity, clinical application, and reproducibility remains unclear [48]. Hence, it is unsurprising that the American Heart Association has not reached a consensus on the application of EBCT as a screening tool for patients with normal renal function. If its ability to predict future cardiovascular events in healthy patients is unknown, even less is understood among patients with ESRD.
Warnings of putative dangers associated with calcium-containing phosphate binders seem premature and perhaps even misplaced in context of the trade-off of risks documented with some, alternative non-calcium containing binders. Prior to the use of calcium salts for controlling phosphorus, ESRD patients were at risk from aluminum intoxication syndromes such as osteomalacia, anemia, and encephalopathy. As advocated by some nephrology thought leaders, the wholesale abandonment of calcium salts may result in hypocalcaemia and the increased emergence of osteopenic bone disease. Moreover, it is important to recognize that differences exist in the efficacy of calcium-containing phosphate binders, which results in differences in the systemic calcium load. Phosphate binders such as calcium acetate have a greater affinity for dietary phosphorus with half the elemental calcium concentration of calcium carbonate [29]. Therefore, with a reduced systemic calcium load, calcium acetate is relatively more effective at lowering the serum phosphorus and PTH concentration, and [calcium]x[phosphorus] [4951].
Clearly, there is a need for prospective, randomized control trials of three types in this area. First, trials need to be conducted to examine the pathobiology of coronary calcification in chronic kidney disease and ESRD. Such studies should examine the difference in rates of calcification as a function of calcium containing vs calcium-free phosphate binders, while controlling for hyperphosphataemia, hypercalcaemia, hyperlipidaemia, and hyperparathyroidism. Secondly, trials need to be conducted to examine the effects of interventions directed toward altering processes associated with ESRD known to induce intimal injury and propagate atherosclerosis such as dyslipidaemia, inflammation, and hyperhomocysteinaemia. Finally, there is a need for outcome-based trials using clinical cardiac events as primary outcomes, rather than intermediate measures like coronary calcification as study endpoints. Until such scientific research is completed, the wholesale abandonment of calcium-containing phosphate binders may be unwarranted given the current level of understanding and scientific evidence.
Notes
Correspondence and offprint requests to: Dr Joseph A. Coladonato, Duke Institute of Renal Outcomes Research and Health Policy, Box 3646, Duke University Medical Center, Durham, NC 27710, USA. Email: joe.coladonato{at}duke.edu
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