COMMENTARY

Should We Target Magnesium Levels in Patients With CKD?

Murray Epstein, MD

Disclosures

August 14, 2015

Cardiovascular disease is the leading cause of death in patients with chronic kidney disease (CKD) and in patients undergoing peritoneal dialysis or hemodialysis. Indeed, the risk of dying from cardiovascular disease is an order of magnitude higher in adults with CKD than in the general population, even after adjustment for age and diabetic status.[1,2] Patients with end-stage renal disease (ESRD) who are undergoing dialysis have twofold to fivefold more coronary artery calcification than age-matched patients with angiographically proven coronary artery disease.[3]

Intimal and medial calcifications are major direct or indirect contributors to cardiovascular disease and excess cardiovascular mortality in patients with CKD.[4,5,6] Thus, it is no surprise that investigators have long focused on disorders of mineral and bone metabolism, primarily involving calcium and phosphorus. Recently we have seen a resurgence of interest in these disorders, specifically in the long-neglected divalent cation magnesium.[7]

The role of magnesium in the pathogenesis of vascular calcification has heretofore not been studied extensively. Magnesium is a natural calcium antagonist; both human and animal studies have shown that low circulating levels of magnesium are associated with enhanced vascular calcification. In vitro and animal studies have suggested that magnesium plays a protective role through multiple molecular mechanisms. Several in vitro studies have shown that magnesium can have an inhibitory effect on hydroxyapatite formation and precipitation, and thus on the calcification process.[8,9,10,11]

The Role of Magnesium in CKD

Clinical evidence also supports the role of magnesium in modulating vascular calcification and consequently survival, and observational studies in patients with CKD illustrate the theoretical construct behind this.[12,13]

Tzanakis and colleagues[12] investigated the role of magnesium in mitral valve calcification in a cross-sectional observational study of patients undergoing chronic hemodialysis in which approximately 40% had mitral annular calcification. They found no significant differences in serum phosphate, calcium, calcium X phosphate product, or intact parathyroid hormone levels in patients with or without mitral annular calcification; however, magnesium levels were significantly lower in patients with calcification. Further statistical analysis showed that patients with serum magnesium levels < 1.23 mmol/L were twice as likely to develop mitral valve calcification as those with magnesium levels > 1.23 mmol/L.

Subsequently, Tzanakis and colleagues[14] conducted a cross-sectional study examining the association of serum and intracellular magnesium levels and carotid intima/media thickness in patients undergoing hemodialysis, using multivariate analysis. These investigators compared 92 patients with stable CKD who were undergoing chronic hemodialysis with 182 age- and sex-matched healthy control participants who had normal renal function.

Tzanakis and colleagues used ultrasonography to demonstrate that intima/media thickness of the common carotid arteries was significantly larger in the hemodialysis patients compared with healthy control participants. They also found that a 0.5-mmol/L change in serum magnesium concentration was associated with a 0.35-mm change in carotid intima/media thickness.

Magnesium and Survival

The potential relationship between serum magnesium levels and survival has been investigated in observational studies of patients with ESRD who were undergoing intermittent hemodialysis. For example, Ishimura and colleagues[15] reported that mortality rates were significantly higher in patients with lower baseline magnesium levels than in patients with higher baseline magnesium levels. After adjustment for such confounding factors as patients' age, sex, duration of hemodialysis, and presence of diabetes, multivariate Cox proportional hazard analysis showed that serum magnesium levels were a significant and independent predictor of overall mortality. Lower serum magnesium concentration was also a significant and independent predictor of death related to noncardiovascular causes but, surprisingly, not of death from cardiovascular causes.

Recently, Tzanakis and colleagues[16] conducted a pilot study to assess whether magnesium slows the progression of arterial calcification in patients receiving hemodialysis. Seventy-two patients with stable ESRD who were undergoing hemodialysis were randomly assigned to receive a regimen containing magnesium carbonate plus calcium acetate as a phosphate binder (the magnesium group) or calcium acetate alone (calcium group). Progression of arterial calcifications were evaluated by plain radiography using a simple vascular calcification score. A multivariate logistic regression analysis found that serum magnesium was an independent predictor of no progression of arterial calcifications. The authors concluded that magnesium probably slows arterial calcification in patients undergoing hemodialysis.

A large, well-designed trial has shown that a drug combining calcium acetate and magnesium carbonate was noninferior in terms of lowering serum phosphate to sevelamer-HCl and had an equally good tolerability profile.[17] Because of the high cost of sevelamer and lanthanum carbonate, the use of magnesium carbonate could be advantageous, and drug acquisition cost savings would compensate for the cost of introducing routine magnesium monitoring, if this is thought to be necessary. Moreover, given the potential cost savings, it may be time to re-investigate magnesium-containing phosphate binders for CKD patients, with further well-designed clinical research using vascular endpoints.[18]

Conclusion and Next Steps

In summary, a growing evidentiary base suggests that magnesium may be beneficial with respect to vascular calcification and survival in patients with CKD and ESRD. These potential benefits include delay of arterial calcification or reduction in carotid artery intima/media thickness. Observational studies complement these findings, demonstrating that low serum magnesium levels may be an independent risk factor for premature death in patients with CKD, and that patients with mildly elevated serum magnesium levels have lower mortality rates related to noncardiovascular causes.

On the basis of this theoretical construct, we clearly need prospective, randomized trials examining the pivotal question of whether interventions to increase serum or cytoplasmic magnesium levels improve cardiovascular outcomes in patients with CKD or ESRD. An attractive experimental approach worthy of consideration may be to replicate the experimental design used in the pilot study by Tzanakis and colleagues,[16] who administered magnesium-containing phosphate binders to patients undergoing hemodialysis. Such an approach should further delineate the potential capability of magnesium to impede the progression of arterial calcification in patients undergoing hemodialysis.

The experimental road to further defining the putative role of magnesium in the pathogenesis of vascular calcification and in improving survival will prove challenging but potentially rewarding.

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