© Borgis - Postępy Nauk Medycznych 10/2015, s. 738-743
Dorota Daniewska, Katarzyna Chmiel-Majewska, *Ryszard Gellert
Stężenie magnezu w osoczu u pacjentów dializowanych – niedoceniany aspekt gospodarki elektrolitowej
Magnesaemia in dialysis patients – the unappreciated feature of mineral metabolism
Department of Nephrology and Internal Medicine, Center of Postgraduate Medical Education, P. Jerzy Popiełuszko Bielański Hospital, Warszawa
Head of Department: prof. Ryszard Gellert, MD, PhD
Stężenia magnezu w osoczu pacjentów dializowanych nie monitoruje się rutynowo, mimo że zaburzenia metabolizmu tego jonu są bardzo częste w tej grupie chorych. W artykule omówiono rolę magnezu jako ważnego, czwartego co do ilości kationu w organizmie oraz częstość występowania i konsekwencje hipo- i hipermagnezemii u pacjentów dializowanych. U pacjentów z niewydolnością nerek oraz dializowanych stężenie magnezu w osoczu może być zarówno podwyższone (z uwagi na brak czynności wydalniczej nerek), prawidłowe, jak i obniżone (z powodu zmniejszonego wchłaniania w przewodzie pokarmowym i usuwania magnezu do płynu dializacyjnego podczas dializy). W populacji ogólnej i u chorych z chorobami sercowo-naczyniowymi wykazano niekorzystny wpływ hipomagnezemii na chorobowość i śmiertelność, i odwrotnie – korzystny efekt suplementacji magnezu. W wielu badaniach eksperymentalnych in vitro i in vivo na modelach zwierzęcych wykazano ochronny wpływ magnezu na układ sercowo-naczyniowy, w tym na hamowanie kalcyfikacji naczyń. Mechanizmy tego protekcyjnego działania magnezu są intensywnie badane. W dużych badaniach obserwacyjnych publikowanych ostatnio potwierdzono wcześniejsze doniesienia o dodatniej korelacji pomiędzy wyższymi stężeniami magnezu u chorych dializowanych, w tym łagodnej hipermagnezemii, a mniejszą chorobowością i śmiertelnością oraz mniejszym stopniem kalcyfikacji naczyń. Stężenie magnezu powinno być zatem rutynowo oznaczane u chorych dializowanych i należy zapobiegać jego niedoborom. Wydaje się, że chociaż łagodna hipermagnezemia wydaje się pozbawiona ryzyka dla pacjentów, a nawet może mieć znaczenie ochronne dla układu krwionośnego chorych, to z uwagi na brak dużych badań interwencyjnych rutynowa suplementacja magnezu nie może być zalecana pacjentom leczonym hemodializami.
Magnesium plasma concentration are seldom controlled in dialysis patients. This article addresses the role of magnesium as the fourth most abundant cation, the consequences of hypo- and hypermagnesaemia, and the prevalence of hypo- and hypermagnesaemia in patients on dialysis. In people with CKD and in dialysed patients, plasma level of magnesium could be above normal, because of the lack of excretion by the kidneys, normal or below normal, as a result of diminished reabsorption and/or removal of magnesium during dialysis. In general population the hypomagnesaemia is a significant predictor of increased cardiovascular morbidity and mortality, and dietary magnesium intake is inversely associated with mortality risk. More and more experimental studies report a protective effect of magnesium on cardiovascular system, including inhibitory effects of magnesium on vascular calcification. Mechanism of this protective magnesium activity is intensely studied. Recently published data obtained from a large group of dialysed patients correlated the higher concentration of magnesium in plasma (including mild hypermagnesaemia) with lower mortality, and lower vascular calcification, which confirmed the earlier observations made on smaller groups of patients. Thus, it seems necessary to monitor the concentration of magnesium in dialysed patients, and prevent its deficiency. Though mild hypermagnesaemia appears of no consequences to the dialysis patients’ health, and even could be protective, the lack of large interventional clinical trials does not allow, at present, to promote magnesium supplementation to increase its level above normal with an intention to prevent vascular calcification and reduce mortality.
Disorders of magnesium homeostasis are common, but seldom monitored in dialysis patients. Mild hypermagnesaemia in this particular group of patients is present more often than in general population, but hypomagnesaemia can also ensue. Can we identify implications for the CRF patients of those disorders and should we monitor the concentration of magnesium in plasma in RRT patients, and try to normalize it?
Data obtained from a large group of patients in Japan show correlation between higher concentration of magnesium in plasma and lower mortality, which confirms the earlier observations made on smaller groups of patients (1-5). A number of experiments conducted during last 15 years showed beneficial effect of magnesium in preventing vascular calcification. In general population and in CVD patients’ hypomagnesaemia was correlated with higher mortality, and higher magnesium levels correlated with better outcomes.
Because of that, many of investigators suggest the necessity of the regular monitoring of the magnesium plasma concentration in dialysis patients.
Magnesium is the fourth most abundant cation in the body, and the second intracellular cation. Almost half of magnesium is located in bones. Only 1-2% is present in extracellular space. About 25-30% of magnesium in serum is bound to proteins, mainly albumin, 5-10% is complexed with nonprotein anions such as bicarbonate, phosphate and citrate; the rest is free, mostly ionized.
In general population, the total and ionized serum magnesium normal concentrations usually range 0.65-1.05 mmol/L and 0.45-0.74 mmol/L, respectively (1 mEq/l = 0.5 mmol about 1.2 mg/dl). Serum magnesium concentration does not strictly reflect the total amount of magnesium in the body.
Kidneys have an important role in magnesium homeostasis: regulation of magnesium excretion is determined by filtration and reabsorption (6, 7). In people with normal renal function ?95% of the 74-100 mmol (1800-2400 mg) of magnesium filtered daily, is reabsorbed in tubules, with the remaining ?5% being excreted in urine. Magnesium reabsorption takes place both in the thick ascending limb (via the paracellular pathway), and in the distal convoluted tubule (via the transcellular route involving transient receptor potential cation channel subfamily melastatin member 6 – TRPM6). In hypermagnesaemia, the fractional excretion of magnesium is high, and it is low in hypomagnesaemia.
In moderate CKD, the increase in fractional excretion of magnesium compensates for the loss of renal function, thus serum levels are maintained within the normal range, but in more advanced renal failure the mechanism becomes inefficient and thus the hypermagnesaemia is quite common. There are many additional factors affecting magnesium concentration in plasma, and magnesium body content (diuretics, proton pump inhibitors, phosphate binders, poor nutrition, acidosis and followed reduced absorption), so in people with CKD the magnesium balance can become negative and lower its plasma concentration.
In dialysed patients the magnesium concentration in dialysate is one of the major determinants of magnesium balance. Ionised magnesium crosses the dialyser and peritoneal membranes freely, and the amount eliminated depends on both the ultrafiltration and the diffusible magnesium concentration gradient between serum and dialysis fluid. Ionized magnesium ranges between 60 and 70% of the total serum value depending on protein concentration and percentage of the complexed magnesium. In most cases, a dialysate magnesium concentration of ?0.5 mmol/L (× 0.962 = 0.46 mmol/L) or lower, results in a diffusive elimination of magnesium.
Mild hypermagnesaemia has been described when using magnesium dialysate concentration of 0.75 mmol/L, in both PD and HD patients, but when lower dialysate concentrations (0.5 and/or 0.25 mmol/L) were used, the results were not that much consistent.
Besides the dialysate concentration, number of factors like diuretics, nutrition, and disorders of gastrointestinal tract, affect the magnesium balance in HD/PD patients. In recent years the role of commonly used proton pump inhibitors, is stressed (8). Proton pump inhibitors decrease the activity of TRPM6 (which is expressed in distal tubule and also in the small intestine brush border membrane, where it increases intestinal magnesium uptake in face of low magnesium intake), and predispose to hypomagnesaemia (9).
Mineral magnesium is involved in several important biochemical reactions, including all ATP transfer reactions (10). Magnesium directly influences vascular tone, baseline tension and vascular responsiveness to vasoconstrictor agents (11).
Magnesium affects calcium ion concentration and its availability at critical sites, acting as a physiologic calcium channel blocker (12). Increased levels of extracellular magnesium inhibit calcium influx. And conversely, reduced extracellular magnesium activates calcium influx via calcium channels. Low intracellular magnesium concentrations stimulate inositol-triphosphate (IP-3)-mediated mobilization of intracellular calcium and reduce Ca2+-ATPase activity. Thus, calcium efflux and sarcoplasmic reticular calcium reuptake are reduced, leading to cytosolic accumulation of calcium and increased intracellular calcium concentration, which is the crucial factor for vasoconstriction. Increased intracellular levels of magnesium result in decreased intracellular free calcium concentration, promoting vasodilation.
Magnesium is also cofactor for acetylcholine-induced endothelium-dependent relaxation. Alterations in extracellular magnesium are able to modify the formation and release of nitric oxide, this way altering arterial smooth muscle tone.
In general population the hypomagnesaemia is a significant predictor of increased cardiovascular morbidity and mortality, favours reduction of HDL and increase of LDL and TG, increases oxidative stress and inflammation, platelet aggregation and insulin resistance (13). Data from recent trial: a study on the Atherosclerosis Risk in Communities (ARIC) cohort (> 14,000 participants), reported an independent association between low magnesium levels and incident heart failure (14). Dietary magnesium intake was inversely associated with mortality risk in people at high risk of CVD in Spanish prospective randomized trial (> 7,200 patients) (15) and in general population (16).
Manifestations of severe hypomagnesaemia include: ataxia, tetany, tremors, depression, muscle fibrillation, and irritability. In less severe cases (mild to moderate) hypomagnesaemia can lead to general weakness, vertigo, electrocardiographic changes (QT prolongation, ST segment shortening), increase in myocardial irritability, reduced myocardial contractility, positive Trousseau and Chvostek signs, hypertension, neuromuscular hyper-excitability with hyper-reflexia, abnormal skeletal function, increased renin and aldosterone secretion and increased incidence of osteoporosis.
Manifestations of severe hypermagnesaemia include: muscle paralysis, apnoea, heart block and cardiac arrest (Mg > 5 mmol/l). Moderate hypermagnesaemia (> 3 mmol/l) can cause: somnolence, areflexia, hypocalcaemia, hypotension, bradycardia electrocardiographic changes (prolongation of PR and QT intervals, increase in QRS duration), pruritus. Hypermagnesaemia > 2 mmol/l can cause hyporeflexia, drowsiness, but that of less than 2 mmol/l is asymptomatic (17, 18).
In RRT patients hypermagnesaemia is seldom above 1.5 mmol/L.
The anxiety about the negative impact of hypermagnesaemia on RRT patients was concerned with bone abnormalities. Even so, the studies assessing the amount of magnesium in bones in patients on RRT are scarce and with the extremely inconsistent results (19-24). It is worth to point out that magnesium constitute only tiny fraction of bone mass – about 0.5%. In several studies authors found the elevated magnesium concentrations in trabecular and cortical bones (20-22), but other group did not find it (25).
Because of its inhibiting effect in mineralisation and influence on PTH secretion, it was suggested that magnesium could be involved in pathogenesis of renal osteodystrophy. On the other hand it was proved that the deficiency of magnesium leads to osteoporosis (26-28).
It was demonstrated that magnesium plasma concentration influence PTH secretion: high magnesium activates extracellular CaSR leading to decreased PTH secretion. On the other hand in patients with severe hypomagnesaemia, at levels < 0.5 mmol of magnesium, secretion of PTH is suppressed (29, 30), and calcium-dependent regulation can be restored by elevating magnesium concentrations. Low Mg levels may reduce serum vitamin D levels and cause vitamin D deficiency (31).
Magnesium deficiency can exacerbate inflammation and in this way lead to osteoporosis. In the rat and/or mouse the Mg deficiency results in increased skeletal substance P, which in turn stimulates production of cytokines. With the use of immunohistocytochemistry, it was found that Mg deficiency resulted in an increase in substance P, TNF alpha and IL-1beta (23).
Several small clinical trials were assessing the influence of Mg on the bone using bone biopsy. In one study, after increasing the serum Mg concentration from 0.96 ± 0.2 mmol/l to 1.54 ± 0.2 mmol/L by using a magnesium phosphate binder for 8 and 20 months, bone histomorphometry (performed in 9 patients) showed no change in mineralization or osteoid formation (21).
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1. Sakaguchi Y, Fujii N, Shoji T et al.: Magnesium modifies the cardiovascular mortality risk associated with hyperphosphatemia in patients undergoing hemodialysis: a cohort study. PLoS One 2014 Dec 29; 9(12): e116273.
2. Meema HE, Oreopoulos DG, Rapoport A: Serum magnesium level and arterial calcification in end-stage renal disease. Kidney Int 1987; 32: 388-394.
3. Tzanakis I, Pras A, Kounali D et al.: Mitral annular calcifications in haemodialysis patients: a possible protective role of magnesium. Nephrol Dial Transplant 1997; 12: 2036-2037.
4. Ishimura E, Okuno S, Kitatani K et al.: Significant association between the presence of peripheral vascular calcification and lower serum magnesium in hemodialysis patients. Clin Nephrol 2007; 68: 222-227.
5. Sakaguchi Y, Fujii N, Shoii T et al.: Hypomagnesaemia is a significant predictor of cardiovascular and non-cardiovascular mortality in patients undergoing hemodialysis. Kidney Int 2014; 85(1): 174-181.
6. Massry SG, Seelig MS: Hypomagnesaemia and hypermagnesaemia. Clin Nephrol 1977; 7: 147-153.
7. Mountokalakis TD: Magnesium metabolism in chronic renal failure. Magnes Res 1990; 3: 121-127.
8. Misra PS, Alam A, Lipman ML, Nessim SJ: The relationship between proton pump inhibitor use and serum magnesium concentration among hemodialysis patients: a cross-sectional study. BMC Nephrol 2015; 16: 136.
9. Bai JP, Hausman E, Lionberger R, Zhang X: Modeling and simulation of the effect of proton pump inhibitors on magnesium homeostasis. 1. Oral absorption of magnesium. Mol Pharm 2012; 9: 3495-3505.
10. Walser M: Magnesium metabolism. Ergeb Physiol 1967; 59: 185-296.
11. Altura BT, Altura BM: Endothelium-dependent relaxation in coronary arteries requires magnesium ions. Br J Pharmacol 1987; 91: 449-451.
12. Iseri LT, French JH: Magnesium: nature‘s physiologic calcium blocker. Am Heart J 1984; 108: 188-193.
13. Qu X, Jin F, Hao Y et al.: Magnesium and the Risk of Cardiovascular Events: A Meta-Analysis of Prospective Cohort Studies. PLoS One 2013; 8(3): e57720.
14. Lutsey PL, Alonso A, Michos ED et al.: Serum magnesium, phosphorus, and calcium are associated with risk of incident heart failure: the Atherosclerosis Risk in Communities (ARIC) Study. Am J Clin Nutr 2014; 100: 756-764.
15. Guasch-Ferrè M, Bulló M, Estruch R et al.: Dietary magnesium intake is inversely associated with mortality in adults at high cardiovascular disease risk. J Nutr 2014; 144: 55-60.
16. Del Gobbo LC, Imamura F, Wu JH et al.: Circulating and dietary magnesium and risk of cardiovascular disease: a systematic review and meta-analysis of prospective studies. Am J Clin Nutr 2013; 98: 160-173.
17. Topf JM, Murray PT: Hypomagnesaemia and hypermagnesaemia. Reviews in Endocrine & Metabolic Disorders 2003; 4: 195-206.
18. Okuno S: Magnesium disorder and its clinical significance in chronic kidney disease. Clinical Calcium 2012; 22: 1243-1249.
19. Drueke T: Does magnesium excess play a role in renal osteodystrophy? Contrib Nephrol 1984; 38: 195-204.
20. Contiguglia SR, Alfrey AC, Miller N, Butkus D: Total-body magnesium excess in chronic renal failure. Lancet 1972; 1: 1300-1302.
21. Berlyne GM, Ben-Ari J, Szwarcberg J et al.: Increase in bone magnesium content in renal failure in man. Nephron 1972; 9: 90-93.
22. Alfrey AC, Miller NL: Bone magnesium pools in uremia. J Clin Invest 1973; 52: 3019-3027.
23. Pellegrino ED, Biltz RM, Letteri JM: Inter-relationships of carbonate, phosphate, monohydrogen phosphate, calcium, magnesium and sodium in uraemic bone: comparison of dialysed and non-dialysed patients. Clin Sci Mol Med 1977; 53: 307-316.
24. Pellegrino ED, Biltz RM: The composition of human bone in uremia. Observations on the reservoir functions of bone and demonstration of a labile fraction of bone carbonate. Medicine (Baltimore)1965; 44: 397-418.
25. Moriniere P, Vinatier I, Westeel PF et al.: Magnesium hydroxide as a complementary aluminium-free phosphate binder to moderate doses of oral calcium in uraemic patients on chronic haemodialysis: lack of deleterious effect on bone mineralisation. Nephrol Dial Transplant 1988; 3: 651-656.
26. Huang JH, Cheng FC, Wu HC: Low Magnesium Exacerbates Osteoporosis in Chronic Kidney Disease Patients with Diabetes. Int J Endocrinol 2015; 2015: 380247.
27. Rude RK, Singer FR, Gruber HE: Skeletal and hormonal effects of magnesium deficiency. J Am Coll Nutr 2009; 28: 131-141.
28. Castiglioni S, Cazzaniga A, Albisetti W, Maier JA: Magnesium and osteoporosis: current state of knowledge and future research directions. Nutrients 2013; 5: 3022-3033.
29. Quitterer U, Hoffmann M, Freichel M, Lohse MJ: Paradoxical block of parathormone secretion is mediated by increased activity of G alpha subunits. J Biol Chem 2001; 276: 6763-6769.
30. Vetter T, Lohse MJ: Magnesium and the parathyroid. Curr Opin Nephrol Hypertens 2002; 11: 403-410.
31. Matsuzaki H, Katsumata S-I, Kajita Y, Miwa M: Magnesium deficiency regulates vitamin D metabolizing enzymes and type II sodium-phosphate cotransporter mRNA expression in rats. Magnesium Research 2013; 26(2): 83-86.
32. Gonella M, Ballanti P, Della RC et al.: Improved bone morphology by normalizing serum magnesium in chronically hemodialyzed patients. Miner Electrolyte Metab 1988; 14: 240-245.
33. D’Haese PC, Couttenye MM, Lamberts LV et al.: Aluminum, iron, lead, cadmium, copper, zinc, chromium, magnesium, strontium, and calcium content in bone of end-stage renal failure patients. Clin Chem 1999; 45: 1548-1556.
34. Spiegel DM, Farmer B: Long-term effects of magnesium carbonate on coronary artery calcification and bone mineral density in hemodialysis patients: a pilot study. Hemodial Int 2009; 13: 453-459.
35. Alabd MA, El-Hammady W, Shawky A et al.: QT Interval and QT Dispersion in Patients Undergoing Hemodialysis: Revisiting the Old Theory. Nephron Extra 2011; 1: 1-8.
36. Kyriazis J, Kalogeropoulou K, Bilirakis L: Dialysate magnesium level and blood pressure. Kidney Int 2004; 66(3): 1221-1231.
37. Gorgels TG, Waarsing JH, de Wolf A: Dietary magnesium, not calcium, prevents vascular calcification in a mouse model for pseudoxanthoma elasticum. J Mol Med (Berl.) 2010; 88: 467-475.
38. Louvet L, Buchel J, Steppan S et al.: Magnesium prevents phosphate-induced calcification in human aortic vascular smooth muscle cells. Nephrol Dial Transplant 2013; 28: 869-878.
39. Neven E, De Schutter TM, Dams G et al.: A magnesium based phosphate binder reduces vascular calcification without affecting bone in chronic renal failure rats. PLoS ONE 2014; 9: e107067.
40. Montezano AC, Zimmerman D, Yusuf H et al.: Vascular smooth muscle cell differentiation to an osteogenic phenotype involves TRPM7 modulation by magnesium. Hypertension 2010; 56: 453-462.
41. Ishimura E, Okuno S, Kitatani K et al.: Significant association between the presence of peripheral vascular calcification and lower serum magnesium in hemodialysis patients. Clin Nephrol 2007; 68: 222-227.
42. Blumenthal NC, Posner AS: Hydroxyapatite: mechanism of formation and properties. Calcif Tissue Res 1973; 13: 235-243.
43. Ennevr J, Vogel JJ: Magnesium inhibition of apatite nucleation by proteolipid. J Dent Res 1981; 60: 838-841.
44. Boskey AL, Posner AS: Effect of magnesium on lipid-induced calcification: an in vitro model for bone mineralization. Calcif Tissue Int 1980; 32: 139-143.
45. Louvet L, Bazin D, Buchel J et al.: Characterisation of calcium phosphate crystals on calcified human aortic vascular smooth muscle cells and potential role of magnesium. PLoS One 2015; 10: e0115342.
46. Nakatani S, Mano H, Ryanghyok IM et al.: Excess magnesium inhibits excess calcium-induced matrix-mineralization and production of matrix gla protein (MGP) by ATDC5 cells. Biochem Biophys Res Commun 2006; 2: 1157-1162.
47. Kircelli F, Peter ME, Ok ES et al.: Magnesium reduces calcification in bovine vascular smooth muscle cells in a dose-dependent manner. Nephrol Dial Transplant 2012; 27: 514-521.
48. Montes de Oca A, Guerrero F, Martinez-Moreno JM et al.: Magnesium Inhibits Wnt/β-Catenin Activity and Reverses the Osteogenic Transformation of Vascular Smooth Muscle Cells. PLoS One 2014; 9(2): e89525.
49. Li Q, Larusso J, Grand-Pierre AE et al.: Magnesium carbonate-containing phosphate binder prevents connective tissue mineralization in Abcc6(-/-) mice – potential for treatment of pseudoxanthoma elasticum. Clin Transl Sci 2009; 2: 398-404.
50. De Schutter TM, Behets GJ, Geryl H et al.: Effect of a magnesium-based phosphate binder on medial calcification in a rat model of uremia. Kidney Int 2013; 83: 1109-1117.
51. Turgut F, Kanbay M, Metin MR et al.: Magnesium supplementation helps to improve carotid intima media thickness in patients on hemodialysis. Int Urol Nephrol 2008; 40(4): 1075-1082.
52. Tzanakis IP, Stamataki EE, Papadaki AN et al.: Magnesium retards the progress of the arterial calcifications in hemodialysis patients: a pilot study. Int Urol Nephrol 2014; 46(11): 2199-2205.
53. De Francisco AL, Leidig M, Covic AC et al.: Evaluation of calcium acetate/magnesium carbonate as a phosphate binder compared with sevelamer hydrochloride in haemodialysis patients: a controlled randomized study (CALMAG study) assessing efficacy and tolerability. Nephrol Dial Transplant 2010; 25(11): 3707-3017.