1 Department of Nephrology and Dialysis, Ospedale San Paolo, University Center, Milan, Italy, 2 Clinical and Laboratory Research Department at Bellco, Bellco SpA, Mirandola, Italy and 3 Department of Internal Medicine, University of Pisa, Pisa, Italy
Introduction
Ectopic calcifications are defined as a process of inappropriate biomineralization occurring in soft tissues [1]. They are typically composed of calcium salts. In uraemic patients such a conditionreferred to as metastatic calcificationis associated with systemic mineral imbalance (hyperphosphataemia and increased calciumphosphate ion product), which is claimed to be responsible for progressive cardiac and vascular damage, leading to invalidating clinical complications and increased mortality risk.
More specifically, Levin et al. [2] showed recently that the critical limit for plasma phosphate is 6.5 mg/dl. Patients with plasma levels above that limit have a 52% higher risk of death from coronary artery disease, compared with the patients whose serum phosphate is below it. Block et al. [3] demonstrated that serum phosphate levels >6.5 mg/dl and a calciumphosphate ion product >72 mg2/dl2 are associated with an 1839% higher risk of death, compared with normal reference groups (namely a serum phosphate of 4.45.5 mg/dl and calciumphosphate product of 4352 mg2/dl2).
Collectively, the data clearly indicate that cardiovascular calcifications of dialysis patients secondary to an increase in phosphate and calcium overload are an important contributor to excessive cardiovascular morbidity and mortality.
Calcium overloadhow?
A high calcium load has been associated with hypercalcaemia (although not necessarily so) and an increased risk of metastatic calcification in uraemic dialysed patients [4,5]. The excess calcium burden can be explained by several mechanisms.
Soft-tissue calcium depositionthe cofactors
Metabolic alkalosis is claimed to act as a trigger of calcium deposition in soft tissues [6]. Considering that higher plasma calcium levels are reached at the end of each dialysis session, just when the patients become alkalotic, it is easy to argue that immediately after the dialysis session there is an enhanced precipitation of calcium. In keeping with this hypothesis, plasma calcium concentrations rapidly decrease to pre-dialysis values, pointing to calcium deposition in tissues.
Adynamic bone disease (ABD) also has a role in soft-tissue calcium deposition: any increase of body calcium burden, occurring in situations such as excessive oral calcitriol therapy, high dialysate calcium, and excessive CaCO3 administration, should lead, at least theoretically, to enhanced calcification of soft tissues and bone. However, in patients affected by ABD, the skeleton is unable to exert its normal role of buffering a calcium overload. Therefore, it must be assumed that most of the calcium excess will be distributed to soft tissues, including in particular cardiac and vascular structures.
Assessing the risk
The increased body burden of calcium may or may not be reflected in elevated serum calcium levels, as normal serum calcium can be maintained in many instances despite a considerable increase in total body burden of calcium, due to calcium deposition in the blood vessels and other extraskeletal tissues [7].
The calciumphosphorous product is considered a theoretical indicator of the risk of mineral crystallization in soft tissues. However, as deposition and dissolution of calcium salts is a dynamic process, there is no absolute level of calciumphosphorous below which precipitation will not occur. Velentzas et al. [8] indicated a threshold product of 60 mg2/dl2, based on a comparison of patients with and without visceral calcifications, suggesting that this level represents the saturation product of the two ions. More recently, a range between 42 and 52 mg2/dl2 was proposed as desirable in the ESRD population [5].
Again about vascular damagethe second part of the story
Recent studies have provided evidence that chronic inflammation plays an important role in the pathogenesis of cardiovascular diseases. Also important is the hypothesis that, in uraemic patients, the chronic inflammatory state could be partly due to the dialysis technique. Thus, the chronic stimulation of monocyte/macrophage components could be a consequence of the interaction between blood and the dialysis membrane, in particular through a back-leakage of endotoxin from a contaminated dialysate across high-flux dialysers [9].
A number of studies have clearly shown that the quality of the dialysate fluid is below current standards. This situation can be considered alarming, when taking into account the discrepancy between such standards and modern dialysis technology. In this context, it has become clear that back-filtration of contaminated dialysate accounts for 50% of the total back-leakable cytokine-inducing substances.
A recent study [10] showed evidence of an increase in intracellular levels of IL-1 and IL-1-receptor antagonist when patients were dialysed for a few months with low volume ultrafiltration that is known to be associated with back-filtration. In these cases, increased IL-1 and IL-1ra levels were associated with elevated IL-6 and C-reactive protein (CRP) levels [11]. There is a general consensus about CRP being a marker of cardiovascular risk both in non-uraemic [12] and uraemic subjects [13]. It could also be a promoter of the progression of atherosclerotic lesions [14,15].
Inflammation and calciuma liaison dangereuse
Considering that the amount of coronary calcium is a marker of atherosclerosis [16], that atherosclerosis is at present viewed as an inflammatory disease [17], that CRP is a marker of cardiovascular risk both in non-uraemic [12] and uraemic subjects [13], that hyperphosphataemia and elevated calciumphosphate product are associated with an increased risk of death [3], a positive correlation between CRP and cardiovascular calcification can be hypothesized. If this is true, inflammation might be a trigger for calcium deposition in the arteries of dialysis patients, peculiarly at the end of each dialysis session when back-filtration might occur, plasma calcium concentrations reach their maximum levels and the patients become alkalotic.
In this context it should also be considered that CRP, being a member of the pentraxin family, binds to damaged tissue in a calcium-dependent manner and shows membrane association with multiple calcium ions [18]. Moreover, CRP binds to enzymatically degraded LDL (E-LDL) particles in early atherosclerotic lesions, inducing complement activation and promoting the development and progression of the atherosclerotic lesion [14].
The finding is also of interest in that the serum concentrations of calcium, calcitriol, and PTH are not correlated with coronary calcification, as assessed by electron beam computed tomography, in non-uraemic subjects undergoing coronary angiography [19]. It suggests that the relationship between coronary atherosclerosis and coronary calcium is not merely a result of hypercalcaemia. Other factors, such as the uraemic state, in addition to an inflammatory reaction or the combination with high phosphate levels, probably play a role in enhanced vascular calcification and the induction of cardiovascular lesions in dialysis patients (Fig. 1).
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Conclusions
Several abnormalities are suspected to have a combined role in promoting the progression of vascular damage in dialysis population. The increase of CRP in stable dialysis patients may be due to the stimulation of monocytes/macrophages by dialysate contaminants and, in turn, may promote by itself atherosclerotic changes in the cardiovascular tree. Concomitant to such an inflammatory state other cofactors are at work: a high oral intake of calcium salts and an excessive vitamin D therapy in a daily fashion, and a positive calcium balance due to supra-normal calcium in the dialysate in an intermittent fashion. In this case metabolic alkalosis may have an additional role in calcium precipitation.
Considering the above-mentioned factors and cofactors it is easy to derive possible therapeutic approaches. It could also be important to tailor the dialysate calcium in order to have an iso-calcic dialysis: a future challenge for the more sophisticated dialysis machines?
Notes
Correspondence and offprint requests to: Diego Brancaccio, MD, Renal Unit-Ospedale San Paolo, Via Di Rudinì 8, I-20142 Milano, Italy. Email: diego.brancaccio{at}tiscalinet.it (or Email 2: nefro{at}hspsanpaolo.mi.it\|[rpar ]\|
References