Magnesium. An update on physiological, clinical and analytical aspects.

Background
Although hypomagnesemia, oxidative stress, and inflammation are involved in the pathogenesis of cardiovascular diseases, there is not a previous description concerning their potential interaction; thus, the aim of this study was to examine the relationship between metabolic syndrome (MetS), hypomagnesemia, inflammation, and oxidative stress.

Methods
Case-control design study. Incident cases of MetS (84 women and 63 men) were compared with healthy control subjects (163 women and 131 men) matched by age and gender. MetS was diagnosed according to the Adult Treatment Panel III (ATP III) criterion. Oxidative stress was defined by serum malondialdehyde concentration (MDA) ≥50 mg/dL, low-grade chronic inflammation by C-reactive protein (CRP) serum levels ≥3 mg/L, and hypomagnesemia by serum magnesium concentrations ≤1.8 mg/dL.

Results
Multivariate analysis adjusted by age, sex, body mass index, waist-to-hip ratio, and total adiposity showed a strong association between MetS and hypomagnesemia (OR 1.9; 95% CI 1.3–7.1), inflammation (OR 1.7; 95% CI 1.4–8.4), and oxidative stress (OR 1.4; 95% CI 0.9–12.6). Additional adjustment by CRP levels showed that MetS remained associated to hypomagnesemia (OR 1.4; 95% CI 1.1–5.9) but not to oxidative stress (OR 1.1; 95% CI 0.9–5.9), and adjusted by MDA levels, MetS remained strongly associated to hypomagnesemia (1.6; CI 95% 1.1–7.4), but not to inflammation (OR 1.05; 95% CI 0.97–14.2). Adjusted by serum magnesium levels, inflammation (OR 1.2; 95% CI 1.1–9.1) and oxidative stress (OR 1.1; 95% CI 1.1–9.7) were slightly associated to MetS.

Conclusions
The interaction of inflammation and oxidative stress is related and increases the risk for MetS, whereas serum magnesium levels and MetS are independently associated. Copyright © 2006 John Wiley & Sons, Ltd.

Hypomagnesemia, oxidative stress, inflammation, and metabolic syndrome.

The kidney has a vital role in magnesium homeostasis and, although the renal handling of magnesium is highly adaptable, this ability deteriorates when renal function declines significantly. In moderate chronic kidney disease (CKD), increases in the fractional excretion of magnesium largely compensate for the loss of glomerular filtration rate to maintain normal serum magnesium levels. However, in more advanced CKD (as creatinine clearance falls <30 mL/min), this compensatory mechanism becomes inadequate such that overt hypermagnesaemia develops frequently in patients with creatinine clearances <10 mL/min. Dietary calcium and magnesium may affect the intestinal uptake of each other, though results are conflicting, and likewise the role of vitamin D on intestinal magnesium absorption is somewhat uncertain. In patients undergoing dialysis, the effect of various magnesium and calcium dialysate concentrations has been investigated in haemodialysis (HD) and peritoneal dialysis (PD). Results generally show that dialysate magnesium, at 0.75 mmol/L, is likely to cause mild hypermagnesaemia, results for a magnesium dialysate concentration of 0.5 mmol/L were less consistent, whereas serum magnesium levels were mostly normal to hypomagnesaemic when 0.2 and 0.25 mmol/L were used. While dialysate magnesium concentration is a major determinant of HD or PD patients’ magnesium balance, other factors such as nutrition and medications (e.g. laxatives or antacids) also play an important role. Also examined in this review is the role of magnesium on parathyroid hormone (PTH) levels in dialysis patients. Although various studies have shown that patients with higher serum magnesium tend to have lower PTH levels, many of these suffer from methodological limitations. Finally, we examine the complex and often conflicting results concerning the interplay between magnesium and bone in uraemic patients. Although the exact role of magnesium in bone metabolism is unclear, it may have both positive and negative effects, and it is uncertain what the optimal magnesium levels are in uraemic patients.

Magnesium in chronic kidney disease Stages 3 and 4 and in dialysis patients.

This review deals with the six main clinical situations related to magnesium or one of its fractions, including ionized magnesium: renal disease, hypertension, pre-eclampsia, diabetes mellitus, cardiac disease, and the administration of therapeutic drugs. Issues addressed are the physiological role of magnesium, eventual changes in its levels, and how these best can be monitored. In renal disease mostly moderate hypermagnesemia is seen; measuring ionized magnesium offers minimal advantage. In hypertension magnesium might be lowered but its measurement does not seem relevant. In the prediction of severe pre-eclampsia, elevated ionized magnesium concentration may play a role, but no unequivocal picture emerges. Low magnesium in blood may be cause for, or consequence of, diabetes mellitus. No special fraction clearly indicates magnesium deficiency leading to insulin resistance. Cardiac diseases are related to diminished magnesium levels. During myocardial infarction, serum magnesium drops. Total magnesium concentration in cardiac cells can be predicted from levels in sublingual or skeletal muscle cells. Most therapeutic drugs (diuretics, chemotherapeutics, immunosuppressive agents, antibiotics) cause hypomagnesemia due to increased urinary loss. It is concluded that most of the clinical situations studied show hypomagnesemia due to renal loss, with exception of renal disease. Keeping in mind that only 1% of the total body magnesium pool is extracellular, no simple measurement of the real intracellular situation has emerged; measuring ionized magnesium in serum has little added value at present.

Magnesium in disease: a review with special emphasis on the serum ionized magnesium.

Background Although several lines of evidence suggest that hypomagnesaemia is a risk factor for developing type 2 diabetes, there are no studies regarding the association between hypomagnesaemia and the risk for developing impaired fasting glucose (IFG) or impaired glucose tolerance (IGT). Our objective was to examine the association between serum magnesium levels and the risk for developing IFG, IGT and type 2 diabetes.



Materials and methods   A total of 1122 individuals (20–65 years of age) were enrolled between 1996 and 1997, and 817 individuals re-examined about 10 years later. New-onset IFG (5·6–7·0 mmol L−1 fasting glucose), IGT (7·8–11·1 mmol L−1 glucose 2-h postload), and type 2 diabetes were determined from the number of subjects who had these conditions at the second examination without evidence that they were present at the first one. The relative risk of new-onset metabolic glucose disorders and diabetes (dependent variables) was computed using Poisson regression model adjusted for age, sex, family history of diabetes, waist circumference and homeostasis model assessment for insulin resistance index. Serum magnesium levels of < 0·74 mmol L−1 (independent variable) defined the exposed group.



Results  At baseline, 420 (51·4%) individuals had hypomagnesaemia. New-onset IFG and IGT was identified in 276 (33·8%) individuals. The relative risk for IFG, IGT and IFG + IGT was 1·11 (95% confidence interval, 0·5–5·1), 1·38 (95% confidence interval, 1·1–6·3) and 1·49 (95% confidence interval, 1·1–4·9), respectively. New-onset diabetes was identified in 78 (9·5%) individuals (relative risk 2·54; 95% confidence interval, 1·1–4·1).



Conclusions  Hypomagnesaemia is independently associated with the development of IGT, IFG + IGT and type 2 diabetes, but not with the development of IFG.

Hypomagnesaemia and risk for metabolic glucose disorders : a 10-year follow-up study

Ionised and total magnesium concentrations were determined in the serum of different groups of patients suffering from renal or hepatic diseases Ionised magnesium was measured by Microlyte 6 (KONE, Espoo, Finland) and total magnesium by atomic absorption spectrometry In renal insufficiency ionised and total magnesium concentrations were almost equally increased In proteinuria with a normal glomerular filtration rate, "pseudohypomagnesaemia" was observed, ie decreased total magnesium concentration in parallel with a decreased albumin concentration with no significant change in the concentration of ionised magnesium Hypermagnesaemia occurred in liver diseases combined with renal insufficiency, whereas "pseudohypomagnesaemia" was most often found in the absence of renal failure Also treatment with an aldosterone antagonist was associated with a normal ionised magnesium concentration, but the total magnesium concentration was decreased; when additional magnesium was administered, the total magnesium concentration approached a normal value, while ionised magnesium slightly exceeded reference values Only during cyclosporin treatment did both ionised and total magnesium concentrations become lowered However, the decrease of total magnesium exceeded that of ionised magnesium due to concomitant hypoalbuminaemia with reduction of the protein-bound fraction It is concluded that especially low total magnesium concentrations should be investigated by measurement of ionised magnesium to exclude "pseudohypomagnesaemia"

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Brunkhorst R

Papers

Ionised and Total Magnesium Serum Concentrations in Renal and Hepatic Diseases