Magnesium and outcomes in patients with chronic kidney disease: focus on vascular calcification, atherosclerosis and survival

Abstract

Patients with chronic kidney disease (CKD) have a high prevalence of vascular calcification, and cardiovascular disease is the leading cause of death in this population. However, the molecular mechanisms of vascular calcification, which are multifactorial, cell-mediated and dynamic, are not yet fully understood. We need to address ways to improve outcomes in CKD patients, both in terms of vascular calcification and cardiovascular morbidity and mortality-and to these ends, we investigate the role of magnesium. Magnesium's role in the pathogenesis of vascular calcification has not been extensively studied. Nonetheless, several in vitro and animal studies point towards a protective role of magnesium through multiple molecular mechanisms. Magnesium is a natural calcium antagonist and both human and animal studies have shown that low circulating magnesium levels are associated with vascular calcification. Clinical evidence from observational studies of dialysis patients has shown that low-magnesium levels occur concurrently with mitral annular calcification, peripheral arterial calcification and increased carotid intima-media thickness. Few interventional studies have been performed. Two interventional studies suggest that there may be benefits such as retardation of arterial calcification and/or reductions in carotid intima-media thickness in response to magnesium supplementation in CKD patients, though both studies have limitations. Finally, observational studies have shown that low serum magnesium may be an independent risk factor for premature death in CKD patients, and patients with mildly elevated serum magnesium levels could have a survival advantage over those with lower magnesium levels.

Keywords: atherosclerosis; chronic kidney disease; magnesium; survival; vascular calcification.

Fig. 1.

Intima and media calcification in CKD patients. Arterial calcifications can be classified as intima calcification, present as discrete plaques with irregular and patchy distribution (A) or as media calcification, present as uniform linear railroad track-type (angiogram-like; B and C). The presence of both, intima and media calcification is reflected as discordances (D). Shown are soft tissue posteroanterior fine-detail native (unenhanced) radiographs of the pelvis and the thigh taken in CKD patients in the recumbent position. A and B, femoral artery; C and D, pelvic artery. With permission from Oxford University Press, London et al. [6].

Fig. 2.

Mechanisms of vascular calcification in CKD patients. Disturbances of mineral and bone metabolism are common in patients with CKD. The progressive loss of kidney function is accompanied—among other changes—by elevated serum FGF23 levels, a decrease in inorganic phosphate excretion and a dysregulation of bone metabolism. These anomalies are intimately interrelated. Indicators of this disturbed state are pathological changes of various biomarkers such as OPG, Klotho, FGF23, PTH and calcitriol. Whether their altered serum levels are the cause or the consequence of the skeletal abnormalities requires further study. The resulting derangements in mineral metabolism, as reflected by altered serum and vascular tissue levels of Ca, P_i and Mg are accompanied by additional metabolic changes and inflammation. This leads to loss of circulating and/or local mineralization inhibitors such as fetuin A, PP_i and MGP, further supporting the development of vascular calcification. Ca, calcium; FGF23, fibroblast growth factor 23; Mg, magnesium; MGP, matrix Gla protein; OPG, osteoprotegerin; P_i , inorganic phosphate; PP_i, inorganic pyrophosphate; PTH, parathyroid hormone. (modified after Schoppet, Shroff et al. [17]).

Fig. 3.

The putative protective roles of magnesium in the course of vascular calcification. Abnormalities in mineral metabolism, particularly hyperphosphataemia as well as the loss of circulating and/or local mineralization inhibitors such as fetuin A, MGP or PP_i, initially lead to the formation and deposition of Ca/P nanocrystals [25, 26]. These nanocrystals are taken up by VSMCs, most likely via endocytosis [29]. The lysosomal degradation of the endocytosed crystals results in an intracellular release of calcium and phosphate. Inorganic phosphate additionally accumulates in the cell via uptake through the sodium-dependent phosphate transporter Pit-1 (and Pit-2) [30, 31]. In an attempt to compensate for excess Ca/P, VSMCs form matrix vesicles loaded with Ca/P products as well as the mineralization inhibitors fetuin A and MGP [32]. The intracellular Ca-burst induced by endocytosed nanocrystals [33] as well as the phosphate uptake [34] trigger VSMC apoptosis, resulting in the formation of Ca/P containing apoptotic bodies [35]. Both apoptotic bodies and matrix vesicles are ultimately causing a positive feedback loop through nanocrystal release into the surrounding milieu, thus amplifying the calcification process. Furthermore, Ca/P nanocrystals as well as P_i induce the expression of genes that promote the calcification/mineralization process such as RUNX2, BMP2 and BGP, while at the same time repressing the expression of MGP or BMP7, factors that are known to inhibit the progression of calcification. This causes a transdifferentiation of VSMCs to osteoblast-like cells, ultimately resulting in vessel calcification. Magnesium interferes with this process of vascular calcification on different levels: firstly, Mg inhibits the transformation from amorphous Ca/P to any apatite (carbonatohydroxyapatite) [36, 37] and forms Mg-substituted tricalcium (whitlockite) under certain conditions, which is more soluble than apatite [37], resulting in smaller, more soluble deposits [37, 38]. Secondly, magnesium functions as a Ca-channel antagonist [39] and thus inhibits the entry of Ca into the cells. Thirdly, within the cell, via TRPM7, Mg restores the balance between the expression of calcification promotors and inhibitors by neutralizing the inhibition of MGP and BMP7 induced by phosphate [40]. Furthermore, it regresses the phosphate- and Ca/P nanocrystal-induced enhanced expression of RUNX2 and BMP2 [41] preventing the VSMCs from osteoblastic conversion and calcification. In addition, magnesium acts on the CaSR [42]; activation of this receptor by calcimimetics has been shown to inhibit VSMC calcification [43]. The underlying molecular mechanisms have not been identified so far. BGP, bone GLA protein, osteocalcin; BMP, bone morphogenetic protein; Ca, calcium; CaSR, calcium-sensing receptor; Mg, magnesium; MGP, matrix Gla protein; P_i, inorganic phosphate; Pit, inorganic phosphate transporter; PP_i, inorganic pyrophosphate; RUNX2, runt-related transcription factor 2, cbfa1, core-binding factor subunit alpha-1; TRPM, transient receptor potential melastatin; VSMC, vascular smooth muscle cell.

Fig. 4.

Effect of diet on the number of calcifications in blood vessels in the kidney cortex of Abcc6^−/− mice. Histograms represent the average number of calcifications per kidney section as a function of diet and diet duration. Diets supplemented with calcium plus magnesium (‘4 × Ca, 4 × Mg’ diet) slowed down calcification significantly [compared with baseline unsupplemented diet or diet supplemented with calcium alone (4 × Ca diet)] after 3, 7 and 12 months (Kruskal–Wallis test, P < 0.05 for all comparisons)] [53]. With kind permission from Springer Science + Business Media, Gorgels et al. [53] (Figure 2).

Fig. 5.

Kaplan–Meier analysis of all-cause mortality rates during a 51-month follow-up of 515 chronic haemodialysis patients. The relative risk of mortality was significantly greater in the group with lower baseline serum magnesium levels (<1.14 mmol/L, n = 261) than in that whith the higher baseline serum magnesium levels (≥1.14 mmol/L; n = 254) [76]. All-cause mortality, P < 0.001 (log-rank test); after adjustment by Cox multivariate analysis, P < 0.05. Reprinted from Ishimura et al. [76], with permission.