Inflammation, CRP, calcium overload and a high calcium–phosphate product: a ‘liaison dangereuse

Diego Brancaccio1,, Ciro Tetta2, Maurizio Gallieni1 and Vincenzo Panichi3

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 condition—referred to as metastatic calcification—is associated with systemic mineral imbalance (hyperphosphataemia and increased calcium–phosphate 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 calcium–phosphate ion product >72 mg2/dl2 are associated with an 18–39% higher risk of death, compared with normal reference groups (namely a serum phosphate of 4.4–5.5 mg/dl and calcium–phosphate product of 43–52 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 overload—how?

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.

(i) Many dialysis patients are affected by secondary hyperparathyroidism and are receiving vitamin D compounds. In this condition parathyroid hormone (PTH) is suppressed by calcitriol itself but also by higher levels of plasma calcium, especially when patients are treated with oral preparations. This increase in plasma calcium is secondary to enhanced intestinal calcium absorption. In this condition, vitamin D also increases intestinal phosphate absorption, thus leading to higher levels of the calcium–phosphate ion product. In other words, the price for suppressing PTH secretion using this approach is very high, considering that the payment is represented by an excess vascular calcification.
(ii) In addition to calcitriol-induced intestinal calcium absorption, the amount of orally ingested calcium is often elevated as dialysis patients usually control their dietary phosphate using high doses of calcium carbonate (2–5 g/day). If we consider that the fraction of intestinal calcium absorption under calcitriol therapy is approximately 20% and that these patients are virtually anuric, it is easy to estimate that the body calcium burden increases by several grams weekly.
(iii) For many years the use of a high dialysate calcium concentration was recommended, and it is still a reality that one-third of end-stage renal disease (ESRD) patients in Italy are treated with a 1.75 mmol calcium concentration in the dialysate. Needless to say that, in this condition, all patients have a positive calcium balance at the end of each dialysis session.

Soft-tissue calcium deposition—the 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 calcium–phosphorous 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 calcium–phosphorous 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 damage—the 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 calcium—a ‘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 calcium–phosphate 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. 1Go).



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Fig. 1. Inflammation as a possible trigger of calcium deposition in soft tissues of dialysis patients: it may happen at the end of each dialysis session when back-filtration may induce CRP increase along with plasma calcium increase and the patients are alkalotic.

 

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 ]\| Back

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