International Journal of Molecular Sciences Review Magnesium Replacement to Protect Cardiovascular and Kidney Damage? Lack of Prospective Clinical Trials Juan R. Muñoz-Castañeda 1,2,† ID , María V. Pendón-Ruiz de Mier 1,2,†, Mariano Rodríguez 1,2,* and María E. Rodríguez-Ortiz 1 1 Nephrology Service, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), University Hospital Reina Sofía, University of Córdoba, 14004 Córdoba, Spain; [email protected] (J.R.M.-C.); [email protected] (M.V.P.-R.d.M.); [email protected] (M.E.R.-O.) 2 Red de Investigación Renal (REDinREN), Instituto de Salud Carlos III, 28029 Madrid, Spain * Correspondence: [email protected]; Tel.: +34-957-213790 † Both authors share first authorship. Received: 9 January 2018; Accepted: 21 February 2018; Published: 27 February 2018 Abstract: Patients with advanced chronic kidney disease exhibit an increase in cardiovascular mortality. Recent works have shown that low levels of magnesium are associated with increased cardiovascular and all-cause mortality in hemodialysis patients. Epidemiological studies suggest an influence of low levels of magnesium on the occurrence of cardiovascular disease, which is also observed in the normal population. Magnesium is involved in critical cellular events such as apoptosis and oxidative stress. It also participates in a number of enzymatic reactions. In animal models of uremia, dietary supplementation of magnesium reduces vascular calcifications and mortality; in vitro, an increase of magnesium concentration decreases osteogenic transdifferentiation of vascular smooth muscle cells. Therefore, it may be appropriate to evaluate whether magnesium replacement should be administered in an attempt to reduce vascular damage and mortality in the uremic population In the present manuscript, we will review the magnesium homeostasis, the involvement of magnesium in enzymatic reactions, apoptosis and oxidative stress and the clinical association between magnesium and cardiovascular disease in the general population and in the context of chronic kidney disease. We will also analyze the role of magnesium on kidney function. Finally, the experimental evidence of the beneficial effects of magnesium replacement in chronic kidney disease will be thoroughly described. Keywords: magnesium; chronic kidney disease; cardiovascular disease; vascular calcification; mortality 1. Magnesium: Metabolism and Physiology Magnesium (Mg) is one of the most abundant cations in organisms [1], and it is involved in a number of physiological processes such as enzymatic reactions and membrane and structural functions [2]. In health, total Mg levels range between 0.7 and 1.4 mM. Johansson et al. compared the levels of ionized and total Mg, finding a weak correlation between both forms [3]. Bone is the main reservoir of Mg (60–65%), buffering changes in Mg level; tissue compartments, mainly skeletal muscle, represent approximately 35% of total Mg, whereas only 1–2% Mg is present in the extracellular fluid [1]. Serum Mg can be found in three different forms: (1) ionized, which mainly exerts biological actions (55–70%), (2) bound to proteins (20–30%) and (3) forming complexes with phosphate, citrate and bicarbonate (5–15%) [2,4]. Assessment of Mg levels is normally performed by measuring total serum Mg. However, Int. J. Mol. Sci. 2018, 19, 664; doi:10.3390/ijms19030664 www.mdpi.com/journal/ijms Int. J.Int. Mol. J. Mol. Sci. Sci.2018 2017, 19, 18, 664, x FOR PEER REVIEW 2 of2 19 of 19 serum Mg. However, this parameter may not reflect accurately the actual Mg availability (ionized thisMg) parameter due to the may fact not that reflect it is influenced accurately by the factors actual such Mg availabilityas pH or the (ionized presence Mg) of other due ligands; to the fact this that is it is influencedof particular by importance factors such in as the pH population or the presence with chronic of other kidney ligands; disease this is(CKD), of particular in which importance advanced in thestage population ionized with Mg levels chronic are kidney affected disease by high (CKD), serum in phosphate which advanced and a high stage anion ionized gap [5]. Mg The levels vast are affectedmajority by highof Mg serum is stored phosphate in bone, and muscle a high and anion at the gap intracellular [5]. The vast level, majority which ofmay Mg further is stored impair in bone, a muscleprecise and evaluation at the intracellular of Mg status level, [6]. which may further impair a precise evaluation of Mg status [6]. AccordingAccording to theto the U.S. U.S. Institute Institute of Medicine of Medicine (Washington (Washington DC), DC), daily daily Mg intakeMg intake in men in andmenwomen and is estimatedwomen is toestimated be 420 and to be 320 420 mg/day, and 320 respectively.mg/day, respectively. Approximately Approximately 50% of Mg50% is of absorbed, Mg is absorbed, although thisalthough proportion this variesproportion according varies toaccording the dietary to the content dietary of content other of elements other elements such as such protein as protein or fiber or [7]. Threefiber different [7]. Three organs different are responsibleorgans are responsible for Mg homeostasis: for Mg homeostasis: intestine, whereintestine, absorption where absorption takes place; bone,takes responsible place; bone, for storage;responsible and for kidneys, storage; controlling and kidneys, Mg excretion.controlling Intestinal Mg excretion. Mg absorption Intestinal occursMg throughabsorption two differentoccurs through paths: two paracellular different transport,paths: paracellular a passive transport, mechanism a passive that representsmechanism 80–90% that represents 80–90% of intestinal uptake, and transcellular absorption, which involves the of intestinal uptake, and transcellular absorption, which involves the participation of the transient participation of the transient receptor potential channel melastatin members 6 and 7 (TRPM 6 and receptor potential channel melastatin members 6 and 7 (TRPM 6 and TRPM7) [8]. As mentioned, bone TRPM7) [8]. As mentioned, bone is essential for Mg storage, and it has been shown that dietary Mg is essential for Mg storage, and it has been shown that dietary Mg influences bone metabolism [9]. influences bone metabolism [9]. Magnesium reabsorption takes place in the various parts of the Magnesiumnephron through reabsorption different takes mechanisms: place in the passive various parace partsllular of the transport nephron occurs through in the different proximal mechanisms: tubule passiveand the paracellular thick ascending transport limb, occurswhere 10–25% in theproximal and 70% of tubule Mg is andabsorbed, the thick respectively. ascending Claudins limb, whereare 10–25%tight-junction and 70% proteins of Mg is that absorbed, determine respectively. the selectivit Claudinsy to small are ions tight-junction and neutral proteins solutes, thatand determinemost of thethem selectivity are expressed to small ions in andthe neutralrenal tubule solutes, [10]. and Claudins most of them16 and are expressed19 have relevant in the renal roles tubule in the [10 ]. Claudinsparacellular 16 and transport 19 have relevantof Mg in rolesthe thick in the ascend paracellularing limb, transport and mutations of Mgin in the their thick genes ascending cause Mg limb, andwasting mutations [11,12]. in their Furthermore, genes cause the MgTRPM6 wasting channel [11 ,enables12]. Furthermore, the active transport the TRPM6 of Mg channel predominantly enables the activein the transport distal convoluted of Mg predominantly tubule, where in approximately the distal convoluted 10% of Mg tubule, is reabsorbed where approximately[8]. A scheme of 10% Mg of Mghomeostasis is reabsorbed is depicted [8]. A scheme in Figure of Mg1. homeostasis is depicted in Figure1. FigureFigure 1. 1.Overview Overview ofof magnesiummagnesium homeostasis. homeostasis. 2. Magnesium and Enzyme Activity 2. Magnesium and Enzyme Activity Magnesium acts as a cofactor in reactions related to glycolysis [13], cell respiration [14,15] and Magnesium acts as a cofactor in reactions related to glycolysis [13], cell respiration [14,15] and the the transport of cations across membranes [16]. Magnesium participates in enzymatic transportreactions of cations[2,17] in across several membranes ways: binding [16]. to Magnesium the ligand, participatesbinding to the in enzymaticactive site reactionsof the enzyme, [2,17] in severalinducing ways: a binding conformational to the ligand, change binding during to thethe active catalytic site ofprocess, the enzyme, promoting inducing the aformation conformational of changemulti-enzyme during the complexes catalytic or process, the combination promoting of some the formationof these. Wh ofen multi-enzyme forming complexes complexes with ATP or the combinationor GTP, Mg of is some the substrate of these. for When kinases forming B, ATPa complexesses or GTPases with ATP and or cyclins. GTP, Mg Furthermore, is the substrate Mg is for kinases B, ATPases or GTPases and cyclins. Furthermore, Mg is directly involved in the activation of enzymes such as phosphofructokinase, adenylate cyclase and Na+ and K+-ATPase [18]. In the context Int. J. Mol. Sci. 2018, 19, 664 3 of 19 of mineral metabolism and its derangements in renal disease, many of these enzymes are key for the normal release of parathyroid hormone (PTH). 3. Magnesium and Apoptosis Apoptosis is a mechanism of programmed cell death, necessary to eliminate damaged or unneeded cells, but it is