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 inves-tigate 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.

Full text

Clin Kidney J (2012) 5[Suppl 1]: i52–i61
doi: 10.1093/ndtplus/sfr167
Magnesium and outcomes in patients with chronic kidney
disease: focus on vascular calcification, atherosclerosis and survival
Ziad A. Massy
1,2
and Tilman B. Dru
¨eke
2
1
Departments of Clinical Pharmacology and Nephrology, Amiens University Hospital, CHU-Amiens South, and
2
INSERM Unit 1088, UFR de
Me
´dicine et de Pharmacie, Universite
´de Picardie Jules Verne, Amiens, France
Correspondence and offprint requests to: Tilman B. Dru
¨eke; E-mail: tilman.drueke@inserm.fr
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 inves-
tigate 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
Introduction
Cardiovascular disease is the leading cause of death in
both chronic kidney disease (CKD) and peritoneal dialysis/
haemodialysis patients. In fact, the risk of dying because of
cardiovascular disease in adults with CKD is about an order
of magnitude higher than for the general population, even
after adjusting for age and diabetic status [1]. It is also
notable that patients with CKD undergoing dialysis have
2- to 5-fold more coronary artery calcification (CAC) than
age-matched individuals with angiographically proven
coronary artery disease [2]. The high incidence of cardio-
vascular mortality appears, at least partially, attributable
to increased medial calcification of the large arteries, in-
cluding the aorta, which in turn can result in increased
arterial wall stiffness and pulse pressure and decreased
myocardial perfusion during diastole [3,4]. However, intimal
calcification associated with atherosclerosis is even more
frequent than medial calcification, especially in patients
with CKD Stages 3–5 before dialysis therapy is started [5].
Both intimal and medial calcification are probably major
direct or indirect contributors to cardiovascular disease
and excess cardiovascular mortality of CKD patients [6,7].
Figure 1 shows typical x-ray aspects of intimal calcification,
medial calcification and mixed intimal and medial calcifica-
tions in pelvic and femoral arteries. Vascular disease preven-
tion is therefore important, with the aim to reduce the
incidence of cardiovascular morbidity and mortality.
While at least some traditional coronary risk factors
(e.g. increased age, dyslipidaemia, diabetes and smoking)
play a role in haemodialysis patients, several non-traditional
factors associated with CKD are also likely to be involved
[8,9]. These include anaemia, uraemic toxins, oxidative
stress, protein glycation and carbamylation and the
disorder of mineral and bone metabolism (CKD–MBD)
[4,8,10,11].
Although being part of CKD–MBD, magnesium’s role in
CKD–MBD has been underestimated and generally neglected.
Here, we review the role of magnesium in vascular calci-
fication with particular focus on CKD and look towards
potential interventions to improve outcomes for this group
of patients.
Magnesium and the pathogenesis of vascular
calcification
Vascular calcification: in vitro evidence and potential
pathogenic mechanisms
The process of vascular calcification may start early during
the course of CKD, prior to the start of dialysis, and worsens
progressively, often in an accelerated fashion compared
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with the general population [12,13]. Disturbances in min-
eral and bone metabolism appear to play a major role in
the pathogenesis and rapid progression of vascular calci-
fication [11,14–16](seeFigure 2 for details). However, it is
notable that compared with calcium and phosphate, the
role of magnesium in this pathologic process has been
the subject of few studies.
The pathogenesis of vascular calcification is not well
understood, but it is likely to be multifactorial [9]. It appears
to be a cell-mediated, dynamic and actively regulated proc-
ess that closely resembles the formation of normal bone
tissue [4,17–20]. Several non-mutually exclusive theories
or mechanisms have been advanced to explain the onset
and progression of vascular calcification, during which a
central role is played by the vascular smooth muscle cells
(VSMCs) that compose the medial layer of the vessel wall.
Figure 3 gives a comprehensive overview of the mechanisms
and factors that act upon VSMCs, influencing their conversion
into osteoblast-like cells—a phenotype that is commonly
found in calcified vessels. Initially, a soluble amorphous cal-
cium–phosphate complex is deposited in presence of exces-
sive calcium phosphate mineral. It is unlikely to cause harm
if stabilized effectively by inhibitory proteins, such as fetuin
A, carboxylated matrix Gla protein (MGP) and osteopontin,
and by the inorganic inhibitory compound pyrophosphate
[17,21–24]. According to three recent reports, however, the
starting point could be the formation of nanocrystals that
could directly stimulate calcification and vascular cell dif-
ferentiation [25,26,27]. Subsequently, when there is an
imbalance between calcification inhibitors and promoters,
amorphous calcium phosphate and/or nanocrystals may
be transformed into the stable hydroxyapatite crystal.
Alterations in calcium and phosphate balance, as observed
in patients with CKD, clearly promote vascular calcification
and may be considered as non-traditional risk factors for
cardiovascular disease in these patients [9,28](Figure 2).
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; Band 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 excre-
tion and a dysregulation of bone metabolism. These anomalies are inti-
mately interrelated. Indicators of this disturbed state are pathological
changes of various biomarkers such as OPG, Klotho, FGF23, PTH and calci-
triol. Whether their altered serum levels are the cause or the consequence
of the skeletal abnormalities requires further study. The resulting derange-
ments 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, osteopro-
tegerin; P
i
, inorganic phosphate; PP
i
, inorganic pyrophosphate; PTH, para-
thyroid hormone. (modified after Schoppet, Shroff et al. [17]).
Magnesium and outcomes in patients with CKD i53
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Calcium phosphate deposition, mainly in the form of car-
bonate and hydroxyapatite, respectively [(Ca,Na)
10
(PO
4
,CO
3
)
6
(OH)
2
,Ca
10
(PO
4
)
6
CO
3
and Ca
10
(PO
4
)
6
(OH)
2
], which also are
the mineral compounds of bone, is the hallmark of vascular
calcification and can occur in the blood vessels, myocar-
dium and cardiac valves [36,27,28,44]. (This issue has
been discussed in greater detail in the review by Jahnen-
Dechent and Ketteler[45] in this supplement.) A recent in vitro
investigation of the role of calcium phosphate deposition in
VSMC calcification suggests that calcium phosphate deposi-
tion is initially a passive phenomenon, which then triggers the
aforementioned osteogenic changes, resulting in the forma-
tion of more organized apatite crystal ultrastructures [26].
An analysis of the crystalline composition of soft tissue
calcification in uraemic patients identified non-visceral and
arterial calcification to be hydroxyapatite, while heart, lung
and skeletal muscle calcification was identified as an amor-
phous or microcrystalline compound composed of calcium,
magnesium and phosphorus [46]. More recently, synchro-
tron X-ray-l-fluorescence and diffraction data were used
to examine vascular calcification. The aortic vessel wall
mineral deposits in calcitriol- and non-calcitriol-treated ro-
dent models of uraemia-induced vascular calcification [44]
were composed of amorphous calcium phosphate precip-
itate, apatite and—in animals treated with calcitriol—also
whitlockite (magnesium-substituted tricalcium phosphate
or calcium magnesium orthophosphate: [(Ca,Mg)
3
(PO
4
)
2
]).
In contrast to this animal work, a very recent detailed inves-
tigation of tissue samples taken from iliac arteries of uraemic
patients revealed the colocalization of hydroxyapatite with
Fig. 3. The putative protective roles of magnesium in the course of vascular calcification. Abnormalities in mineral metabolism, particularly hyperphos-
phataemia 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.
i54 Z.A. Massy and Q.T.B. Dru
¨eke
by Tilman Drueke on March 2, 2012http://ckj.oxfordjournals.org/Downloaded from

whitlockite in three of six patients, indicating that this type
of calcium phosphate crystals is not only found in soft
tissue calcifications but also in the vascular space [27].
The presence of magnesium in calcification is not unex-
pected as it inhibits the formation of apatite and stabilizes
amorphous calcium phosphate [36,22,47]. In addition,
other inhibitors of calcifications, namely calcium binding
or calcification-inhibitory proteins such as fetuin A, osteo-
pontin and MGP, were found in close association with
microcalcifications [27].
Several in vitro studies have shown that magnesium can
have an inhibitory effect on hydroxyapatite formation and
precipitation, as well as on the calcification process. Posner’s
group showed in the 1970s and 1980s that magnesium
stabilized amorphous calcium phosphate and inhibited
the formation of calcium-acidic phospholipid–phosphate
complexes in metastable calcium phosphate solutions
[48,49]. Of interest, Bennett et al. [50] found that mag-
nesium was also able to inhibit calcium pyrophosphate
dihydrate crystal formation in vitro. More recently, the effect
of magnesium was examined on in vitro VSMC transforma-
tion into osteoblast-like cells and calcification [40]. The ad-
dition of 2.0–3.0 mM magnesium to a high-phosphate
medium prevented osteogenic differentiation and calcifi-
cation, in part via the restoration of the activity of the
cation channel known as transient receptor potential
melastatin 7 (TRPM7). Magnesium also increased the ex-
pression of anti-calcification proteins, including osteo-
pontin and MGP [40]. Furthermore, it was shown that
magnesium can stimulate the calcium-sensing receptor
(CaSR), which is expressed on VSMCs [51,52]. Stimulation
of the CaSR by calcimimetics reduced mineral deposition in
VSMCs and delayed the progression of both aortic calcifi-
cation and atherosclerosis in uraemic apoE
(/)
mice [43].
The exact underlying mechanisms have not been resolved
so far but this suggests that one of the mechanisms of how
magnesium influences VSMC calcification might be via the
CaSR. Thus, magnesium could protect against vascular cal-
cification via multiple molecular mechanisms.
Potential mechanisms of the inhibitory effects of mag-
nesium in the calcification process are shown in Figure 3.
Evidence from animal experiments
Low serum levels of magnesium are associated with vas-
cular calcification, both in humans and in a number of
experimental animal studies [53–56]. Several of the animal
studies have demonstrated that changes in dietary mag-
nesium levels can cause or prevent vascular calcification
[53–55]. A rat model consisting of aortic transplantation
associated with medial calcification of the grafted vessel
was used to show that dietary supplementation with a
combination of magnesium, alkali citrate and bases was
capable of preventing aorta transplant-induced calcifica-
tion [54]. The effect of dietary magnesium and calcium has
also been examined in the Abcc6
/
mouse, a pseudo-
xanthoma elasticum (PXE) mouse model which mimics
the clinical features of PXE (a genetic disorder character-
ized by calcification of connective tissue in skin, Bruch’s
membrane of the eye and blood vessel walls) [53]. Disease
severity was measured by quantifying calcification after up
to 12 months dietary treatment. An increase in dietary
intake of calcium and magnesium resulted in significantly
fewer calcifications of kidney blood vessels than mice
given an unsupplemented diet or fed a calcium-enriched
diet alone (both P <0.05) [53](Figure 4). In the same
mouse model, it was shown that treatment with the phos-
phate binder magnesium carbonate prevented the onset
as well as the progression of calcification, whereas treat-
ment with lanthanum carbonate had no effect [57].
The effect of phosphate and magnesium intake has been
investigated in a mouse model (DBA/2) associated with dys-
trophic cardiac calcification [55]. DBA/2 mice with either a
low-magnesium or a high-phosphate intake developed
marked cardiac calcifications; moreover, a combination
of low-magnesium and high-phosphate intake caused se-
vere calcification of cardiac and renal tissues. However, when
increasing dietary magnesium content and reducing dietary
phosphate, cardiac calcification could be partially prevented.
Magnesium is also considered to be ‘a natural calcium
antagonist’ as one of its major functions in biological sys-
tems is to modulate the neuromuscular activity of calcium
ions [39,58]. Thus, contractility of all types of muscle is
dependent upon the actions and interactions of these two
divalent cations. The magnesium ion can block calcium
movement across VSMC membranes and lower peripheral
and cerebral vascular resistance [39]. More generally speak-
ing, magnesium deficiency appears to enhance the activity
of calcium in the body, while an excess of magnesium
may block it, and as such magnesium may help to control
cardiovascular function [58].
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 3Ca, 4 3Mg’ diet)
slowed down calcification significantly [compared with baseline unsupple-
mented diet or diet supplemented with calcium alone (4 3Ca diet)] after 3,
7 and 12 months (Kruskal–Wallis test, P <0.05 for all comparisons)] [53].
With kind permission from Springer Science 1Business Media, Gorgels et al.
[53](Figure 2).
Mechanisms of vascular calcification are poorly
understood but are likely to be multifactorial,
cell-mediated and dynamic processes.
Low serum magnesium levels are associated with
vascular calcification in human and in animal
studies. Animal studies show that dietary mag-
nesium can prevent, or help mitigate, vascular
calcification.
Magnesium has potential to protect against vas-
cular calcification via multiple molecular mecha-
nisms.
Magnesium and outcomes in patients with CKD i55
by Tilman Drueke on March 2, 2012http://ckj.oxfordjournals.org/Downloaded from

Clinical evidence for the role of magnesium in
calcification, atherosclerosis and survival
Vascular calcification, atherogenesis and magnesium:
observational studies
The influence of serum magnesium levels on vascular cal-
cification has been suspected for a considerable time, as
shown by a number of observational studies in patients with
CKD (Table 1). In an early observational study, 44 end-stage
renal disease (ESRD) patients receiving peritoneal dialysis
therapy were followed up for a mean duration of 27 months
[59]. Half of the patients (n¼22) developed peripheral
arterial calcifications (detected in the hands, ankles or
feet), while the remainder either did not develop any calci-
fications or had calcifications that regressed. The arterial
calcification group had significantly lower mean serum
magnesium levels (SD) than the group without calcifi-
cations [1.11 0.21 mmol/L (2.69 0.52 mg/dL) and
1.24 0.21 mmol/L (3.02 0.51 mg/dL), respectively;
P<0.001]. Moreover, there were no significant between-
group differences in parameters such as serum concen-
trations of calcium, phosphorus, calcium 3phosphorus
product, total alkaline phosphatases or intact parathyroid
hormone (iPTH). Although the difference between serum
magnesium levels in the calcification and no-calcification/
calcification regression groups was striking, the study was
limited by the semi-quantitative nature of vascular calcifi-
cation assessment. Nevertheless, these results suggested
that there may be a role for modest hypermagnesaemia as
a preventative strategy for arterial calcification in patients
with ESRD.
Another observational study has been conducted in
390 patients undergoing maintenance haemodialysis that
excluded patients with diabetes, and which used hand ra-
diography to detect visible calcification of hand arteries in
an examiner blinded manner [56]. Phalangeal vessel calci-
fication was detected in 52 patients (13%). Mean serum
magnesium levels (SD) measured over a 4-month period
were significantly lower in patients with vascular calcifica-
tion [1.11 0.12 mmol/L (2.69 0.28 mg/dL)] than in those
without [1.14 0.14 mmol/L (2.78 0.33 mg/dL); P <0.05].
In addition, multivariate analysis showed that serum mag-
nesium concentration was a significant independent factor
associated with vascular calcification [odds ratio 0.28;
95% confidence interval (CI) 0.09–0.92 per 0.41 mmol/L
(1 mg/dL) increase in serum magnesium levels; P ¼0.036]
after adjustment for age, sex, duration of haemodialysis
and serum calcium, phosphate and iPTH concentrations.
However, as in the study by Meema et al., the authors only
used a semi-quantitative assessment of the small hand
arteries by X-ray examination [56,59].
Mitral valve calcification is common in patients under-
going haemodialysis, and magnesium may exert a protec-
tive role against this type of cardiovascular calcification as
well [60,61]. This question has been investigated in a
cross-sectional observational study of chronic haemodial-
ysis patients (n¼56) in which 23 patients (41%) had mitral
annular calcification [60]. There were no significant differ-
ences between patients with or without mitral annular
calcification with regard to serum phosphate, calcium,
calcium 3phosphate product or iPTH, but magnesium lev-
els were significantly lower in patients with calcification
(P <0.05). Further statistical analysis showed that patients
Table 1. Observational and interventional studies investigating the influence of serum magnesium levels on vascular calcification
a
Authors (year) Patients Study design Parameter Assessment technique P-value
b
Observational studies
Ishimura et al. (2007) [56] 390 (non-diabetic
haemodialysis)
Prospective single
blind follow-up
over 4 months
Calcification of
the hand arteries
Radiographic findings
of the hands
0.036
Tzanakis et al. (2004) [62] 93 (haemodialysis)
and 182 age- and
sex-matched healthy
controls
Cross-sectional
analysis
Carotid intima–media
thickness
B-mode ultrasound 0.001
Tzanakis et al. (1997) [60] 56 (haemodialysis) Retrospective
analysis
of 8 years
Mitral annular
calcification
Doppler
echocardiography
0.008
Meema et al. (1987) [59] 44 (CAPD) Prospective
follow-up
Progression/regression
of arterial calcification
Radiographic surveys 0.001
Interventional studies
Spiegel et al. (2009) [71] 7 (haemodialysis) Prospective
interventional
follow-up
over 18 months
(Mg carbonate)
CAC Electron beam
tomography
0.0737
c
Turgut et al. (2008) [75] 47 (haemodialysis) Prospective
interventional
follow-up over
2 months
(Mg citrate)
Intima–media thickness
of the carotid artery
Ultrasound 0.014
d
a
Results indicate that higher serum magnesium correlates with reduced vascular calcification and reduced intima–media thickness.
b
P-values indicate the significance level related to lower and higher serum magnesium levels or
c
progression vs baseline and
d
intervention versus no intervention, respectively. CAPD, continuous ambulatory peritoneal dialysis; CAC, coronary artery calcification.
i56 Z.A. Massy and Q.T.B. Dru
¨eke
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with serum magnesium levels <1.23 mmol/L (3.0 mg/dL)
were twice as likely to develop mitral valve calcification as
those with magnesium levels >1.23 mmol/L (3.0 mg/dL)
(v
2
¼6.98; P ¼0.008). Moreover, multiple logistical regres-
sion showed that serum magnesium levels could predict
the occurrence of mitral annular calcification with 86%
accuracy when controlling for patients’ age and biochemical
factors other than magnesium levels [60].
More recently, Tzanakis et al. [62] in a cross-sectional study
reported a negative association of both serum and intracel-
lular magnesium levels with carotid intima–media thickness
in patients undergoing haemodialysis, using multivariate
analysis. The authors compared 93 stablechronic haemodial-
ysis patients with 182 age- and sex-matched healthy control
subjects with normal renal function. Intima–media thickness
of both common carotids was assessed by ultrasonography:
it was found to be significantly larger in the haemodialysis
patients than the healthy controls (P <0.001). Thus, for a
0.5 mmol/L (1.0 mEq/L) change in serum magnesium concen-
trations, a 0.35-mm change in carotid intima–media thick-
ness was observed (P ¼0.01).
Results from an observational study conducted within the
general population in Japan (n¼728) point to a similar direc-
tion. Lower serum magnesium levels were significantly and
independently associated with greater mean intima–media
thickness (P ¼0.004) and the risk of at least two carotid pla-
ques (P ¼0.03) [63] (see also Geiger and Wanner [64]inthis
supplement). Magnesium deficiency has also been reported
to be related to the progression of atherosclerosis in several
studies, including the observational Atherosclerosis Risk in
Communities (ARIC) Study in middle-aged adults [65,66].
Overall, these observational data suggest that magne-
sium may play an important protective role in the devel-
opment and/or acceleration of arterial atherosclerosis in
both patients with chronic kidney failure and in the general
population since carotid intima–media thickness as meas-
ured by ultrasonography is thought to be a surrogate marker
for increased risk of myocardial infarction and stroke [67].
Thus, it appears that magnesium deficiency, caused either
by poor diet or impaired magnesium metabolism, may be
the missing link between various cardiovascular risk factors
and atherosclerosis [68]. This issue is discussed further in
the review by Geiger and Wanner [64]inthissupplement.
Vascular calcification, atherogenesis and magnesium:
intervention studies
Given the potential involvement of low-magnesium levels
in vascular calcification, as shown by various observational
studies, some interventional studies have investigated the
use of magnesium, though as yet there is no hard evidence
in patients with ESRD (Table 1). A case study has described
the resolution of soft tissue calcification after treatment
with a dialysate containing a high concentration of mag-
nesium [69]. Interestingly, clinical symptoms of soft tissue
calcification such as joint swelling or pain reappeared
when magnesium concentration in dialysate was subse-
quently reduced and again improved when the high dial-
ysate magnesium level was re-instituted.
A pilot study conducted in 30 stable haemodialysis pa-
tients suggested that oral magnesium carbonate was gen-
erally well tolerated and effective in controlling serum
phosphorus while reducing elemental calcium ingestion
[70]. Following-on from this study, magnesium carbonate
was given as a long-term phosphate binder to seven hae-
modialysis patients, all of whom had baseline CAC scores
>30 and were treated with a dialysate containing 1.25
mmol/L (2.5 mEq/L) calcium and 0.375 mmol/L (0.75
mEq/L) magnesium, three times weekly [71]. This open-
label, prospective pilot study evaluated changes in CAC
scores from baseline and at 6, 12 and 18 months using
electron beam computed tomography. There was no sig-
nificant CAC score progression throughout the study (me-
dian per cent change in CAC score from baseline was 8, 4
and 8% at 6, 12 and 18 months, respectively). Further-
more, a paired test for directional change of CAC score
was not statistically significant from baseline to 18 months
(P ¼0.0737). However, this study did not have a control
group. For comparison, in other studies that included com-
parator groups, CAC in patients with CKD showed progres-
sion rates from baseline to month 12 in the range of
5–33% for sevelamer and 25–75% for calcium-containing
phosphate binders. [72–74].
A larger study randomized 47 chronic haemodialysis pa-
tients to two groups: a magnesium group in which patients
were given oral magnesium citrate at a dosage of 610 mg
every other day in addition to daily oral calcium acetate
and a control group in which patients received only cal-
cium acetate as a phosphate binder [75]. The study lasted
2 months. Mean serum calcium and phosphorus concen-
trations did not change in either group. Serum magnesium
concentration also did not change in the control group but
increased in the magnesium group by the end of the study.
Magnesium supplementation was generally well tolerated:
none of the patients presented with signs of magnesium
toxicity such as arrhythmia or neuromuscular manifesta-
tions, none developed severe hypermagnesaemia and only
one discontinued treatment because of diarrhoea. Carotid
intima–media thickness was measured by ultrasound.
At baseline, both groups had similar carotid intima–media
thickness values. After 2 months, mean carotid intima–
media thickness was reduced significantly in the magne-
sium group (0.70 versus 0.97 mm for left carotid artery,
P¼0.001; 0.78 versus 0.95 mm for right carotid artery,
P¼0.002) but not in the control group. In addition, there
was a significant inverse association between the abso-
lute change in serum magnesium concentrations and in
right (but not left) carotid intima–media thickness after
2 months of magnesium treatment (R¼0.443; P ¼0.014).
Serum PTH levels were also reduced in the magnesium
group, but not in the control group. This led the authors
Evidence based on observational studies:
ESRD patients with peripheral arterial calcifica-
tion had lower mean serum magnesium levels
than those without calcifications or whose calci-
fications had regressed.
Mitral annular calcification in chronic haemodial-
ysis patients was strongly associated with low
serum magnesium levels.
The above effects were independent of several
other commonly involved factors such as serum
phosphate, calcium, calcium 3phosphate pro-
duct or parathyroid hormone (PTH) levels.
There was a strong association between lower
serum magnesium levels and increased carotid
intima–media thickness in patients undergoing
long-term haemodialysis treatment.
Similar associations were also observed in the
general population.
Magnesium and outcomes in patients with CKD i57
by Tilman Drueke on March 2, 2012http://ckj.oxfordjournals.org/Downloaded from

to suggest that the beneficial effect of magnesium sup-
plementation on carotid intima–media thickness might,
among other factors, also be linked to a better control of
hyperparathyroidism. However, baseline serum PTH was
two times higher in the magnesium group than the con-
trol group. The authors concluded that magnesium sup-
plementation might be useful in reducing the progression
of atherosclerosis in chronic dialysis patients [75].
Magnesium and survival of haemodialysis
patients: observational studies
The potential relationship between serum magnesium lev-
els and survival has been investigated in 515 ESRD patients
undergoing intermittent haemodialysis treatment [76].
During a mean (SD) follow-up of 51 (17) months, 103
patients died (41 from cardiovascular causes). When ana-
lysing the results according to the patients’ baseline serum
magnesium levels, mortality rates were significantly
higher in the group with lower baseline magnesium levels
[<1.14 mmol/L (2.77 mg/dL), n¼261] than in the group
with higher baseline magnesium levels [1.14 mmol/L
(2.77 mg/dL); n¼254] (P <0.001) (Figure 5). It is important
to note, at this point, that serum magnesium concentra-
tion at baseline correlated strongly with concentrations
1 year later (r¼0.835, P ¼0.0001). Multivariate Cox pro-
portional hazard analysis showed that serum magnesium
levels were a significant and independent predictor of
overall mortality {hazard ratio [per 0.41 mmol/L (1 mg/dL)
increase in magnesium], 0.485 [95% CI, 0.241–0.975],
P¼0.0424} after adjustment for confounding factors such
as patients’ age, sex, duration of haemodialysis and pres-
ence of diabetes. Lower serum magnesium concentration
was also a significant and independent predictor of death
owing to non-cardiovascular causes [hazard ratio 0.318
(95% CI, 0.132–0.769), P ¼0.011], but not for death from
cardiovascular causes [hazard ratio 0.983 (95% CI, 0.313–
3.086), P ¼0.976]. The authors concluded that it might be
worthwhile considering a higher dietary intake of magne-
sium and/or an adjustment of dialysate magnesium
concentrations.
Another observational, retrospective and as yet pre-
liminary study showed an association between increased
serum magnesium concentrations and reduced relative risk
of mortality in a large haemodialysis patient cohort [77,78].
The analysis was done in a subgroup of all chronic haemo-
dialysis patients treated at Fresenius Medical Care North
America facilities, n¼110 271 (total sample) who had at
least one serum magnesium result between 1 October
and 31 December 2007 (baseline) and who survived until
1 January 2008, n¼27 544 (subsample). The subgroup
was considered to be representative of the entire patient
cohort. Mortality was followed until the end of 2008 and Cox
models were constructed. A quarter of the patients (27 544
of 110 271) had serum magnesium levels recorded at base-
line. The mean (SD) concentration was 0.93 0.16 mmol/L
(2.26 0.38 mg/dL). Compared with magnesium levels of
0.80–0.95 mmol/L (1.94–2.31 mg/dL) (mid-normal levels,
used as a reference), the unadjusted hazard ratio for mor-
tality in the observation period decreased significantly with
increasing magnesium concentrations [beginning at 0.95–
1.05 mmol/L (2.31–2.55 mg/dL); P <0.0001], to a hazard
ratio of 0.68 [magnesium concentration >1.15 mmol/L
(>2.80 mg/dL); P <0.0001]. Results for Cox models were
similar when adjusting for case mix or for five quality indi-
cators at baseline (serum albumin and phosphorus, haemo-
globin, eKt/Vand vascular access). More recently, similar
results were found in a European database [79]. However,
it must be pointed out that both these studies have not yet
been published in a peer review journal.
What is clearly needed are prospective randomized trials
examining the question whether increased serum or cy-
toplasmic magnesium levels or a magnesium intake in
amounts such as those provided by magnesium containing
phosphate binders is beneficial or not, in terms of hard
outcomes in patients with CKD.
Suggestive evidence from interventional studies:
Long-term administration of oral magnesium sup-
plements to CKD patients on intermittent haemo-
dialysis therapy might retard arterial calcification
(based on a pilot study).
Oral magnesium supplementation over a 2-month
period led to a significant reduction in carotid
intima–media thickness.
0
20
40
60
Percent survival
80
100
Follow-up period (months)
0 10 20 30 40 50 60
Higher Mg group
Lower Mg group
p < 0.001 log-rank test
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 se-
rum magnesium levels (<1.14 mmol/L, n¼261) than in that whith the
higher baseline serum magnesium levels (1.14 mmol/L; n¼254) [76].
All-cause mortality, P <0.001 (log-rank test); after adjustment by Cox mul-
tivariate analysis, P <0.05. Reprinted from Ishimura et al. [76], with per-
mission.
Magnesium and survival in haemodialysis patients:
(partly based on data presented in abstract form
only)
Patients with slightly elevated serum magnesium
concentrations may have a survival advantage.
Low serum magnesium concentrations may be
independent predictors of death.
i58 Z.A. Massy and Q.T.B. Dru
¨eke
by Tilman Drueke on March 2, 2012http://ckj.oxfordjournals.org/Downloaded from

Conclusions
A growing body of evidence from in vitro investigations,
animal models and both observational as well as interven-
tional clinical studies point to the possibility that low mag-
nesium levels are associated with vascular calcification.
Moreover, several observational studies suggest a relation-
ship between increased serum magnesium concentrations
and better survival rates for patients receiving long-term
dialysis treatment. Preliminary results from an uncon-
trolled interventional trial suggest that long-term inter-
vention with magnesium in dialysis patients may retard
arterial calcification. However, many questions remain
unanswered and hard evidence is as yet lacking. In order
to conclusively show possible benefits and to demonstrate
the absence of harm with the long-term intake of oral
magnesium in patients with CKD, we still have to wait for
the results of randomized controlled trials.
Acknowledgements. The authors thank Dr Richard Clark and
Dr Martina Sintzel for providing writing and editorial assistance
on behalf of Fresenius Medical Care Deutschland GmbH. Fresenius
also made an unrestricted educational grant to meet the cost
of preparing this article. These declarations are in line with the
European Medical Writers’ Association guidelines.
Conflict of interest statement. Z.A.M. has received speakers’ hono-
raria and research grants from Amgen, Genzyme, Fresenius Medical
Care and Shire. T.B.D has received advisor/consultancy honoraria
from Abbott, Amgen, Baxter, Fresenius, Genzyme, KAI Pharma-
ceuticals, KfH-Stiftung Pra
¨ventivmedizin, Leo, Mitsubishi, Roche,
Vifor and Theraclion; speaker honoraria from Abbott, Amgen, Chugai,
Genzyme, Kirin, Roche, Takeda and grant/research support from
Amgen, Baxter and Shire.
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Magnesium and outcomes in patients with CKD i61
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