Phosphorus Control
Figure 2: Distribution of Serum Magnesium Concentrations in Patients with Stage 5 Chronic Kidney Disease Receiving Haemodialysis
Normal range (1.6–2.6mg/dl)
100 120 140 160 180 200
20 40 60 80
0
1.4 1.6 1.8 2.0 2.2 2.4 2.6 2.8 Serum magnesium (mg/dl)
Source: Okuna and Inaba, 2007.34
Diabetes, dyslipidaemia and metabolic syndrome are all well- established risk factors for atherosclerosis. All have been associated with low Mg serum levels and/or low Mg intake in large epidemiological studies.
A cohort of the already-mentioned ARIC study, consisting only of African-American or Caucasian participants without diabetes at baseline (n=12 and 128, respectively), revealed a 55% increased risk of developing diabetes with low serum Mg levels (<0.7mmol/l) compared with serum Mg levels above 0.9mmol/l. However, this association was only shown for white and not for black participants, and no correlation between the risk of diabetes and Mg intake was observed.26
On the other hand, the Women’s Health Study, which included 39,345 women ≥45 years of age followed up for six years, found a significant inverse association between Mg intake and the risk of developing type 2 diabetes (p=0.007).27
In addition, Mg intake was found to be
inversely associated with the incidence of metabolic syndrome in 4,637 young adults followed up for 15 years; significant differences between the quartiles of Mg intake were observed for glucose, blood pressure, high-density lipoprotein (HDL) cholesterol, triglyderides and waist circumference.28
Some study data suggest that increasing plasma Mg levels may help regulate arterial blood pressure via a reduction in systemic vascular resistance29
and may exert an antithrombotic effect by inhibiting the
upregulation of type 1 plasminogen activator inhibitor (PAI-1). PAI-1 has been found to be increased in several prothrombotic clinical conditions. Inhibiting PAI-1 activity is believed to retard the development of atherosclerotic lesions.30
Various animal studies have shown that Mg deficiency induces inflammatory responses characterised by leukocyte and macrophage activation, the release of inflammatory cytokines and acute-phase proteins and excessive production of free radicals. Inflammation contributes to the pro-atherogenic changes in lipoprotein metabolism, endothelial dysfunction, thrombosis and hypertension.31
Mg deficiency also initiates a systemic stress response through activating neuroendocrinological pathways. This is a result of changes
30
3.0 3.2 3.4 3.6 3.8
in the secretion or activity of neuromediators, including acetylcholine and catecholamine. These effects increase the risk of atherosclerosis, hypertension, arrhythmia and chronic myocardial ischaemia. While the in vivo data are extensive, there are few data on the effect of Mg on immune, neurological and biochemical functions in the human body.
Several authors have commented that much further investigation is needed.31,32
The Role of Magnesium in Chronic Kidney Disease and Associated Cardiovascular Disease
Fractional Mg excretion increases with decreasing renal function in order to maintain serum levels within the normal range.33
However,
when the glomerular filtration rate falls below 30ml/min, hyper- magnesaemia becomes common and levels of Mg are generally elevated in CKD stage 5.34
The severity of hypermagnesaemia is
variable and this affects the symptoms observed. Although mild (<2mmol Mg⁄l), hypermagnesaemia is usually asymptomatic. At levels between 2 and 3mmol/l, lethargy, drowsiness and hyporeflexia may occur.3
However, in CKD stage 5, hypermagnesaemia is usually mild
and asymptomatic. The distribution of serum Mg concentrations was demonstrated in a Japanese study of 714 patients with CKD stage 5 receiving haemodialysis (see Figure 2).34
The Mg levels in this study
were generally elevated but were normally distributed, with the modal level at the high end of the normal range (2.4–2.6mg/dl).
In the absence of renal excretion, dialysate Mg concentration is the crucial factor controlling serum Mg levels. The gradient between ionised Mg concentration in the serum and in the dialysate determines the direction and magnitude of diffusion and thus the dialytic balance. Kelber et al. measured Mg mass transfer using dialysate Mg concentrations of 0, 0.25 and 0.75mmol/l in eight patients undergoing high-efficacy haemodialysis.35
Baseline serum Mg
was 1.36±0.008mmol/l. By measuring Mg in the spent dialysate, they recorded Mg removal of 486±44, 306±69 and 56±50mg, respectively (p<0.001). However, there was wide interindividual variability in Mg balance, with actual uptake of Mg in three patients, particularly with the 0.75mmol/l Mg dialysate. Consequently, in patients with serum levels closer to the normal range (0.62–1.02mmol/l), uptake of Mg can be assumed when a dialysate Mg concentration higher than 0.5mmol/l is used.
In patients with CKD stage 5, the leading cause of mortality and morbidity is CVD: 42% of patients receiving dialysis in the Dialysis Outcome Practice Patterns Study were diagnosed with coronary artery disease.36
Mg levels in the lower range of normal are strongly
associated with vascular calcification and cardiovascular mortality among patients with CKD stage 5. The incidence of CVD is significantly greater in patients with Mg deficiency. Vascular calcification is an important factor in the pathogenesis of CVD and is a strong risk factor for increased morbidity and mortality in patients with CKD stage 5. Various studies have reported increased levels of vascular calcification in patients with CKD stage 5 compared with the general population.37,38
In a study using computed tomography (CT) scanning of young adults with CKD stage 5, vascular calcification was absent in those under 20 years of age; however, it was present in 14 of 16 patients between 20 and 30 years of age.38
However, in a group of 60 control subjects
with normal kidney function, vascular calcification was present in only three individuals. In another study that included 49 patients who were
EUROPEAN NEPHROLOGY
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