Magnesium and Progression of Chronic Kidney Disease: Benefits Beyond Cardiovascular Protection?

  • Yusuke Sakaguchi
    Address correspondence to Yusuke Sakaguchi, MD, PhD, Department of Comprehensive Kidney Disease Research, Osaka University Graduate School of Medicine, 2-2, Yamada-oka, Suita 565-0871, Japan.
    Department of Comprehensive Kidney Disease Research, Osaka University Graduate School of Medicine, Suita, Japan and Department of Nephrology, Osaka University Graduate School of Medicine, Suita, Japan
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  • Takayuki Hamano
    Department of Comprehensive Kidney Disease Research, Osaka University Graduate School of Medicine, Suita, Japan and Department of Nephrology, Osaka University Graduate School of Medicine, Suita, Japan
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  • Yoshitaka Isaka
    Department of Comprehensive Kidney Disease Research, Osaka University Graduate School of Medicine, Suita, Japan and Department of Nephrology, Osaka University Graduate School of Medicine, Suita, Japan
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      Experimental and clinical studies have demonstrated that magnesium deficiency leads to hypertension, insulin resistance, and endothelial dysfunction, and is associated with an increased risk of cardiovascular events. Given that cardiovascular disease and CKD share similar risk factors, the low magnesium status may also contribute to CKD progression. In fact, lower serum magnesium levels and lower dietary magnesium intake are associated with an increased risk of incident CKD and progression to end-stage kidney disease. Because these associations are independent of traditional risk factors, other pathways might be involved in the relationship between magnesium deficiency and the risk of CKD progression. Recent evidence has shown that magnesium suppresses phosphate-induced vascular calcification. Magnesium impairs the crystallization of calcium phosphate—more specifically, the maturation of calciprotein particles. Considering that phosphate overload causes kidney damage, magnesium might counteract the phosphate toxicity to the kidney, as in the case of vascular calcification. This hypothesis is supported by an in vitro observation that magnesium alleviates proximal tubular cell injury induced by high phosphate. Potential usefulness of magnesium as a treatment option for phosphate toxicity in CKD should be further investigated by intervention studies.

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        • de Baaij J.H.
        • Hoenderop J.G.
        • Bindels R.J.
        Magnesium in man: implications for health and disease.
        Physiol Rev. 2015; 95: 1-46
        • Hamano T.
        • Sakaguchi Y.
        • Fujii N.
        • Isaka Y.
        Clinical features of CKD-MBD in Japan: cohort studies and registry.
        Clin Exp Nephrol. 2017; 21: 9-20
        • Lansman J.B.
        • Hess P.
        • Tsien R.W.
        Blockade of current through single calcium channels by Cd2+, Mg2+, and Ca2+: voltage and concentration dependence of calcium entry into the pore.
        J Gen Physiol. 1986; 88: 321-347
        • Yoshimura M.
        • Oshima T.
        • Matsuura H.
        • Ishida T.
        • Kambe M.
        • Kajiyama G.
        Extracellular Mg2+ inhibits capacitative Ca2+ entry in vascular smooth muscle cells.
        Circulation. 1997; 95: 2567-2572
        • Maier J.A.
        Endothelial cells and magnesium: implications in atherosclerosis.
        Clin Sci (Lond). 2012; 122: 397-407
        • Ascherio A.
        • Rimm E.B.
        • Giovannucci E.L.
        • et al.
        A prospective study of nutritional factors and hypertension among US men.
        Circulation. 1992; 86: 1475-1484
        • Joosten M.M.
        • Gansevoort R.T.
        • Mukamal K.J.
        • et al.
        • PREVEND Study Group
        Urinary magnesium excretion and risk of hypertension: the prevention of renal and vascular end-stage disease study.
        Hypertension. 2013; 61: 1161-1167
        • Kass L.
        • Weekes J.
        • Carpenter L.
        Effect of magnesium supplementation on blood pressure: a meta-analysis.
        Eur J Clin Nutr. 2012; 66: 411-418
        • Suárez A.
        • Pulido N.
        • Casla A.
        • Casanova B.
        • Arrieta F.J.
        • Rovira A.
        Impaired tyrosine-kinase activity of muscle insulin receptors from hypomagnesaemic rats.
        Diabetologia. 1995; 38: 1262-1270
        • McNair P.
        • Christensen M.S.
        • Christiansen C.
        • Madsbad S.
        • Transbøl I.
        Renal hypomagnesaemia in human diabetes mellitus: its relation to glucose homeostasis.
        Eur J Clin Invest. 1982; 12: 81-85
        • Nair A.V.
        • Hocher B.
        • Verkaart S.
        • et al.
        Loss of insulin-induced activation of TRPM6 magnesium channels results in impaired glucose tolerance during pregnancy.
        Proc Natl Acad Sci U S A. 2012; 109: 11324-11329
        • Gommers L.M.
        • Hoenderop J.G.
        • Bindels R.J.
        • de Baaij J.H.
        Hypomagnesemia in type 2 diabetes: a vicious circle?.
        Diabetes. 2016; 65: 3-13
        • Dong J.Y.
        • Xun P.
        • He K.
        • Qin L.Q.
        Magnesium intake and risk of type 2 diabetes: meta-analysis of prospective cohort studies.
        Diabetes Care. 2011; 34: 2116-2122
        • Song Y.
        • He K.
        • Levitan E.B.
        • Manson J.E.
        • Liu S.
        Effects of oral magnesium supplementation on glycaemic control in type 2 diabetes: a meta-analysis of randomized double-blind controlled trials.
        Diabet Med. 2006; 23: 1050-1056
        • Paravicini T.M.
        • Yogi A.
        • Mazur A.
        • Touyz R.M.
        Dysregulation of vascular TRPM7 and annexin-1 is associated with endothelial dysfunction in inherited hypomagnesemia.
        Hypertension. 2009; 53: 423-429
        • Shechter M.
        • Sharir M.
        • Labrador M.J.
        • Forrester J.
        • Silver B.
        • Bairey Merz C.N.
        Oral magnesium therapy improves endothelial function in patients with coronary artery disease.
        Circulation. 2000; 102: 2353-2358
        • Barbagallo M.
        • Dominguez L.J.
        • Galioto A.
        • Pineo A.
        • Belvedere M.
        Oral magnesium supplementation improves vascular function in elderly diabetic patients.
        Magnes Res. 2010; 23: 131-137
        • Cunha A.R.
        • D'El-Rei J.
        • Medeiros F.
        • et al.
        Oral magnesium supplementation improves endothelial function and attenuates subclinical atherosclerosis in thiazide-treated hypertensive women.
        J Hypertens. 2017; 35: 89-97
        • Del Gobbo L.C.
        • Imamura F.
        • Wu J.H.
        • de Oliveira Otto M.C.
        • Chiuve S.E.
        • Mozaffarian D.
        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
        • 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: e57720
        • Larsson S.C.
        • Orsini N.
        • Wolk A.
        Dietary magnesium intake and risk of stroke: a meta-analysis of prospective studies.
        Am J Clin Nutr. 2012; 95: 362-366
        • Khan A.M.
        • Lubitz S.A.
        • Sullivan L.M.
        • et al.
        Low serum magnesium and the development of atrial fibrillation in the community: the Framingham Heart Study.
        Circulation. 2013; 127: 33-38
        • Stepura O.B.
        • Martynow A.I.
        Magnesium orotate in severe congestive heart failure (MACH).
        Int J Cardiol. 2009; 131: 293-295
        • Tin A.
        • Grams M.E.
        • Maruthur N.M.
        • et al.
        Results from the Atherosclerosis Risk in Communities study suggest that low serum magnesium is associated with incident kidney disease.
        Kidney Int. 2015; 87: 820-827
        • Joosten M.M.
        • Gansevoort R.T.
        • Bakker S.J.
        • PREVEND Study Group
        Low plasma magnesium and risk of developing chronic kidney disease: results from the PREVEND Study.
        Kidney Int. 2015; 87: 1262-1263
        • Rebholz C.M.
        • Tin A.
        • Liu Y.
        • et al.
        Dietary magnesium and kidney function decline: the Healthy Aging in Neighborhoods of Diversity Across the Life Span study.
        Am J Nephrol. 2016; 44: 381-387
        • Farhadnejad H.
        • Asghari G.
        • Mirmiran P.
        • Yuzbashian E.
        • Azizi F.
        Micronutrient intakes and incidence of chronic kidney disease in adults: Tehran Lipid and Glucose study.
        Nutrients. 2016; 8: 217
        • Van Laecke S.
        • Nagler E.V.
        • Verbeke F.
        • Van Biesen W.
        • Vanholder R.
        Hypomagnesemia and the risk of death and GFR decline in chronic kidney disease.
        Am J Med. 2013; 126: 825-831
        • Sakaguchi Y.
        • Shoji T.
        • Hayashi T.
        • et al.
        Hypomagnesemia in type 2 diabetic nephropathy: a novel predictor of end-stage renal disease.
        Diabetes Care. 2012; 35: 1591-1597
        • Pham P.C.
        • Pham P.M.
        • Pham P.A.
        • et al.
        Lower serum magnesium levels are associated with more rapid decline of renal function in patients with diabetes mellitus type 2.
        Clin Nephrol. 2005; 63: 429-436
        • Ibels L.S.
        • Alfrey A.C.
        • Haut L.
        • et al.
        Preservation of function in experimental renal disease by dietary restriction of phosphate.
        N Engl J Med. 1978; 298: 122-126
        • Neves K.R.
        • Graciolli F.G.
        • dos Reis L.M.
        • et al.
        Adverse effects of hyperphosphatemia on myocardial hypertrophy, renal function, and bone in rats with renal failure.
        Kidney Int. 2004; 66: 2237-2244
        • Cozzolino M.
        • Dusso A.S.
        • Liapis H.
        • et al.
        The effects of sevelamer hydrochloride and calcium carbonate on kidney calcification in uremic rats.
        J Am Soc Nephrol. 2002; 13: 2299-2308
        • Nagano N.
        • Miyata S.
        • Obana S.
        • et al.
        Sevelamer hydrochloride, a phosphate binder, protects against deterioration of renal function in rats with progressive chronic renal insufficiency.
        Nephrol Dial Transplant. 2003; 18: 2014-2023
        • Koizumi T.
        • Murakami K.
        • Nakayama H.
        • Kuwahara T.
        • Yoshinari O.
        Role of dietary phosphorus in the progression of renal failure.
        Biochem Biophys Res Commun. 2002; 295: 917-921
        • Ohnishi M.
        • Razzaque M.S.
        Dietary and genetic evidence for phosphate toxicity accelerating mammalian aging.
        FASEB J. 2010; 24: 3562-3571
        • Schwarz S.
        • Trivedi B.K.
        • Kalantar-Zadeh K.
        • et al.
        Association of disorders in mineral metabolism with progression of chronic kidney disease.
        Clin J Am Soc Nephrol. 2006; 1: 825-831
        • Norris K.C.
        • Greene T.
        • Kopple J.
        • et al.
        Baseline predictors of renal disease progression in the African American study of hypertension and kidney disease.
        J Am Soc Nephrol. 2006; 17: 2928-2936
        • Voormolen N.
        • Noordzij M.
        • Grootendorst D.C.
        • et al.
        High plasma phosphate as a risk factor for decline in renal function and mortality in pre-dialysis patients.
        Nephrol Dial Transplant. 2007; 22: 2909-2916
        • Chue C.D.
        • Edwards N.C.
        • Davis L.J.
        • et al.
        Serum phosphate but not pulse wave velocity predicts decline in renal function in patients with early chronic kidney disease.
        Nephrol Dial Transplant. 2011; 26: 2576-2582
        • O'Seaghdha C.M.
        • Hwang S.J.
        • Muntner P.
        • et al.
        Serum phosphorus predicts incident chronic kidney disease and end-stage renal disease.
        Nephrol Dial Transplant. 2011; 26: 2885-2890
        • Zoccali C.
        • Ruggenenti P.
        • Perna A.
        • et al.
        Phosphate may promote CKD progression and attenuate renoprotective effect of ACE inhibition.
        J Am Soc Nephrol. 2011; 22: 1923-1930
        • Bellasi A.
        • Mandreoli M.
        • Baldrati L.
        • et al.
        Chronic kidney disease progression and outcome according to serum phosphorus in mild-to-moderate kidney dysfunction.
        Clin J Am Soc Nephrol. 2011; 6: 883-891
        • Sim J.J.
        • Bhandari S.K.
        • Smith N.
        • et al.
        Phosphorus and risk of renal failure in subjects with normal renal function.
        Am J Med. 2013; 126: 311-318
        • Chartsrisak K.
        • Vipattawat K.
        • Assanatham M.
        • et al.
        Mineral metabolism and outcomes in chronic kidney disease stage 2–4 patients.
        BMC Nephrol. 2013; 14: 14
        • Mehrotra R.
        • Peralta C.A.
        • Chen S.C.
        • et al.
        No independent association of serum phosphorus with risk for death or progression to end-stage renal disease in a large screen for chronic kidney disease.
        Kidney Int. 2013; 84: 989-997
        • Aihara K.
        • Byer K.J.
        • Khan S.R.
        Calcium phosphate-induced renal epithelial injury and stone formation: involvement of reactive oxygen species.
        Kidney Int. 2003; 64: 1283-1291
        • Cai M.M.
        • Smith E.R.
        • Holt S.G.
        The role of fetuin-A in mineral trafficking and deposition.
        Bonekey Rep. 2015; 4: 672
        • Kuro-O M.
        The FGF23 and Klotho system beyond mineral metabolism.
        Clin Exp Nephrol. 2017; 21: 64-69
        • Aghagolzadeh P.
        • Bachtler M.
        • Bijarnia R.
        • et al.
        Calcification of vascular smooth muscle cells is induced by secondary calciprotein particles and enhanced by tumor necrosis factor-α.
        Atherosclerosis. 2016; 251: 404-414
        • Smith E.R.
        • Hanssen E.
        • McMahon L.P.
        • Holt S.G.
        Fetuin-A-containing calciprotein particles reduce mineral stress in the macrophage.
        PLoS One. 2013; 8: e60904
        • Kutikhin A.G.
        • Velikanova E.A.
        • Mukhamadiyarov R.A.
        • et al.
        Apoptosis-mediated endothelial toxicity but not direct calcification or functional changes in anti-calcification proteins defines pathogenic effects of calcium phosphate bions.
        Sci Rep. 2016; 6: 27255
        • Wong T.Y.
        • Wu C.Y.
        • Martel J.
        • et al.
        Detection and characterization of mineralo-organic nanoparticles in human kidneys.
        Sci Rep. 2015; 5: 15272
        • Kuro-o M.
        Klotho, phosphate and FGF-23 in ageing and disturbed mineral metabolism.
        Nat Rev Nephrol. 2013; 9: 650-660
        • Termine J.D.
        • Peckauskas R.A.
        • Posner A.S.
        Calcium phosphate formation in vitro. II. Effects of environment on amorphous-crystalline transformation.
        Arch Biochem Biophys. 1970; 140: 318-325
        • Pasch A.
        • Farese S.
        • Gräber S.
        • et al.
        Nanoparticle-based test measures overall propensity for calcification in serum.
        J Am Soc Nephrol. 2012; 23: 1744-1752
        • Keyzer C.A.
        • de Borst M.H.
        • van den Berg E.
        • et al.
        Calcification propensity and survival among renal transplant recipients.
        J Am Soc Nephrol. 2016; 27: 239-248
        • Bressendorff I.
        • Hansen D.
        • Schou M.
        • et al.
        Oral magnesium supplementation in chronic kidney disease stage 3-4: efficacy, safety, and effect on serum calcification propensity—a prospective randomised double-blinded placebo-controlled clinical trial.
        Kidney Int Rep. 2017; 2: 380-389
        • Montezano A.C.
        • 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
        • Kircelli F.
        • Peter M.E.
        • Sevinc Ok E.
        • et al.
        Magnesium reduces calcification in bovine vascular smooth muscle cells in a dose-dependent manner.
        Nephrol Dial Transplant. 2012; 27: 514-521
        • Salem S.
        • Bruck H.
        • Bahlmann F.H.
        • et al.
        Relationship between magnesium and clinical biomarkers on inhibition of vascular calcification.
        Am J Nephrol. 2012; 35: 31-39
        • Louvet L.
        • Büchel J.
        • Steppan S.
        • Passlick-Deetjen J.
        • Massy Z.A.
        Magnesium prevents phosphate-induced calcification in human aortic vascular smooth muscle cells.
        Nephrol Dial Transplant. 2013; 28: 869-878
        • Montes de Oca A.
        • Guerrero F.
        • Martinez-Moreno J.M.
        • et al.
        Magnesium inhibits Wnt/β-catenin activity and reverses the osteogenic transformation of vascular smooth muscle cells.
        PLoS One. 2014; 9: e89525
        • Louvet L.
        • Bazin D.
        • Büchel J.
        • Steppan S.
        • Passlick-Deetjen J.
        • Massy Z.A.
        Characterisation of calcium phosphate crystals on calcified human aortic vascular smooth muscle cells and potential role of magnesium.
        PLoS One. 2015; 10: e0115342
        • Xu J.
        • Bai Y.
        • Jin J.
        • et al.
        Magnesium modulates the expression levels of calcification-associated factors to inhibit calcification in a time-dependent manner.
        Exp Ther Med. 2015; 9: 1028-1034
        • Bai Y.
        • Zhang J.
        • Xu J.
        • et al.
        Magnesium prevents β-glycerophosphate-induced calcification in rat aortic vascular smooth muscle cells.
        Biomed Rep. 2015; 3: 593-597
        • Louvet L.
        • Metzinger L.
        • Büchel J.
        • Steppan S.
        • Massy Z.A.
        Magnesium attenuates phosphate-induced deregulation of a microRNA signature and prevents modulation of Smad1 and Osterix during the course of vascular calcification.
        Biomed Res Int. 2016; 2016: 7419524
        • Diaz-Tocados J.M.
        • Peralta-Ramirez A.
        • Rodríguez-Ortiz M.E.
        • et al.
        Dietary magnesium supplementation prevents and reverses vascular and soft tissue calcifications in uremic rats.
        Kidney Int. 2017; 92: 1084-1099
        • Sakaguchi Y.
        • Fujii N.
        • Shoji T.
        • et al.
        Committee of Renal Data Registry of the Japanese Society for Dialysis Therapy. Magnesium modifies the cardiovascular mortality risk associated with hyperphosphatemia in patients undergoing hemodialysis: a cohort study.
        PLoS One. 2014; 9: e116273
        • Sakaguchi Y.
        • Iwatani H.
        • Hamano T.
        • et al.
        Magnesium modifies the association between serum phosphate and the risk of progression to end-stage kidney disease in patients with non-diabetic chronic kidney disease.
        Kidney Int. 2015; 88: 833-842
        • Van de Cauter J.
        • Sennesael J.
        • Haentjens P.
        Long-term evolution of the mineral metabolism after renal transplantation: a prospective, single-center cohort study.
        Transplant Proc. 2011; 43: 3470-3475
        • Van Laecke S.
        • Van Biesen W.
        • Verbeke F.
        • De Bacquer D.
        • Peeters P.
        • Vanholder R.
        Posttransplantation hypomagnesemia and its relation with immunosuppression as predictors of new-onset diabetes after transplantation.
        Am J Transplant. 2009; 9: 2140-2149
        • Huang J.W.
        • Famure O.
        • Li Y.
        • Kim S.J.
        Hypomagnesemia and the risk of new-onset diabetes mellitus after kidney transplantation.
        J Am Soc Nephrol. 2016; 27: 1793-1800
        • Van Laecke S.
        • Van Biesen W.
        Hypomagnesaemia in kidney transplantation.
        Transpl Rev (Orlando). 2015; 29: 154-160
        • Holzmacher R.
        • Kendziorski C.
        • Michael Hofman R.
        • Jaffery J.
        • Becker B.
        • Djamali A.
        Low serum magnesium is associated with decreased graft survival in patients with chronic cyclosporin nephrotoxicity.
        Nephrol Dial Transplant. 2005; 20: 1456-1462