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Magnesium Balance in Chronic and End-Stage Kidney Disease
ACKD
Magnesium Balance in Chronic and End-Stage Kidney Disease Ben Oliveira, John Cunningham, and Stephen B. Walsh This article explores the effects of CKD and end-stage kidney disease on magnesium balance. In CKD, there is decreased glomerular filtration of magnesium. Decreased tubular reabsorption can compensate to a degree, but once CKD stage 4 is reached there is a tendency toward hypermagnesemia. In dialysis, magnesium balance is dependent on the constituents of the dialysate that the blood is exposed to. The concentration of dialysate magnesium is just one of the factors that need to be considered. During transplantation, there are particular effects of immunosuppressants that can affect the magnesium balance and need to be considered by the clinician. Q 2018 by the National Kidney Foundation, Inc. All rights reserved. Key Words: Electrolytes, Magnesium, Kidney disease
INTRODUCTION Magnesium is the eighth most abundant element within the earth’s crust, the second most prevalent intracellular cation after potassium, is crucial for the functioning of ATP as well as the synthesis of both DNA and RNA, and is a cofactor in over 300 enzymatic reactions. Important links exist between this alkali earth metal and vascular calcification, cardiovascular disease, and CKD development.1-3 Magnesium balance is regulated via absorption from the gastrointestinal tract and elimination by the kidneys. The kidney excretion of magnesium depends on the glomerular filtration rate (GFR) that is then modulated by tubular reabsorption. As the GFR falls, the kidney’s ability to excrete magnesium declines, and thus, there is a tendency for hypermagnesemia in CKD. However, there are other factors that contribute to magnesium balance in CKD, such as drugs (e.g. proton-pump inhibitors [PPIs], calcineurin inhibitors [CNIs]), vitamin D status, and the presence of diabetes. For patients on dialysis, magnesium excretion depends largely on the magnesium gradient across the dialysis membrane and other factors related to the patient and dialysate. NORMAL MAGNESIUM BALANCE To understand magnesium dysregulation in CKD, it is necessary briefly to touch on magnesium homeostasis in health. Extracellular magnesium accounts for 1% of total body magnesium with most of the remaining 99% sequestered in bones and muscles. Magnesium is absorbed in the gut and predominantly excreted by the kidneys. The fractional absorption of dietary magnesium is typically around 30%, and this can increase and decrease in response to both low and high magnesium diets, respectively.4,5 Two transport mechanisms have been defined for intestinal magnesium absorption: paracellular and transcellular routes. Paracellular transport accounts for 80-90% of total absorption and is a passive process driven by the relatively high luminal concentration of magnesium and the electropositive transluminal gradient.6 Transcellular magnesium relies on transport through the transient receptor potential channel melastatin member 6 (TRPM6) and TRPM7 channels.6 Intestinal absorption may be influenced by vitamin D status7,8 but Adv Chronic Kidney Dis. 2018;25(3):291-295
this is controversial9,10 and kidney TRPM6 expression per se does not appear to be influenced by vitamin D.11 The main excretory pathway for magnesium is kidney where the fractional excretion can change from nearly 0.5% in hypomagnesemia to greater than 70% in hypermagnesemia.12 Magnesium is freely filtered (70-80% of magnesium is ultrafiltratable, the rest is protein bound) at the glomerulus, but under normal circumstances, approximately 95% is reabsorbed along the course of the kidney tubule. Bulk magnesium transport (up to 70%) occurs in the thick ascending limb with passive paracellular magnesium uptake. This process is driven by the luminal positive gradient driven by K1 recycling via apical NKCC2 and ROMK transporters in thick ascending limb cells. The tight junction proteins claudin-16 and claudin19 comprise the paracellular route for magnesium reabsorption driven by this gradient. Fine-tuning of magnesium reabsorption occurs in the distal convoluted tubule (DCT) and is an active process driven by TRPM6. The magnesium extruding transport protein on the basolateral cell membrane has yet to be identified. Regulation of kidney magnesium handling in the DCT is partly under control of parathyroid hormone (PTH) which increases tubular reabsorption of the cation.13 Hypomagnesemia stimulates PTH synthesis and release via the calcium sensing receptor (CaSR) in the parathyroid glands, though with potency 2 to 3 times less than that of calcium.14 However, in the DCT, the potency of magnesium and calcium as activators of the CaSR appears equal.15 In the parathyroids, the CaSR exhibits a biphasic response in that very low levels of magnesium can reduce the sensitivity of the CaSR to calcium, as well as to magnesium itself, leading to decreased PTH release and profound hypocalcemia, a scenario that requires correction of the hypomagnesemia to restore the responsiveness of the CaSR to calcium and From the Centre for Nephrology, Royal Free Hospital, London, UK. Financial Disclosure: The authors declare that they have no relevant financial interests. Address correspondence to Ben Oliveira, North Middlesex University Hospital, Renal Medicine, London N181QX, UK. E-mail: [email protected] Ó 2018 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 https://doi.org/10.1053/j.ackd.2018.01.004
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allow appropriate release of PTH.16 PTH secretion is mediated by cyclic adenosine monophosphate. Cyclic adenosine monophosphate is dependent on magnesium for its production and this explains the unresponsiveness of the parathyroids in profound hypomagnesemia.17 Other players involved in magnesium regulation in the DCT include epidermal growth factor and estrogen which activate transcription of TRPM6.18,19
calcification and mortality. The pathogenesis of vascular calcification in kidney disease is complicated and beyond the scope of this article. In brief, calcium phosphate can influence vascular smooth muscle cells (VSMCs) to become osteoblast like, promoting vascular calcification.29 It has been shown that in vitro magnesium is able to prevent this process from occurring. In vitro studies have shown that magnesium inhibits osteogenic transformation and calcification of VSMCs, which is probably mediated via ASSESSING MAGNESIUM STATUS TRPM7 channels.30 It also modulates the expression of several anticalcification proteins possibly via restoring miAlthough the usual starting point is measurement of blood magnesium concentration, this compartment only consticroRNA signature at the site of calcification.30,31 Magnesium can also activate the CaSR found in VSMCs, tutes about 1% of the body’s total stores. A person in negative and this has also been shown to attenuate vascular magnesium balance will mobilize stores in muscle and bone calcification.32 Hypomagnesemia can, therefore, lead to to maintain serum levels. Thus, total magnesium stores have increased vascular calcification which will increase cardioto be quite low before this is reflected by the serum concentravascular risk burden. Indeed tion. Indeed, healthy volunstudies have shown that low teers on magnesium deficient CLINICAL SUMMARY magnesium levels are associdiets did not deplete their ated with death in dialysis serum levels after 92 days.20 There is a tendency toward hypermagnesemia in CKD. patients.33 There is also evidence that Constituents of the diasylate are the main factors governing A J-shaped curve describes those with serum levels in magnesium status in dialysis patients. the relationship between the the low-normal range (0.75– serum magnesium and mor0.80 mmol/L) may be func In transplantation, calcineurin inhibitors can lead to tality. An observational tionally magnesium deficient hypomagnesemia. study of over 65,000 patients as they display increased found that a magnesium chronic disease risk akin to level above 2.3 mg/dL was a predictor of adverse outthose with levels less than 0.75 mmol/L.21-23. Urinary excretion is modified within a few days of a change in comes.34 A similar relationship is seen in dialysis patients, 20 but in contrast to the previous study, the lowest level of gastrointestinal absorption. Thus, the urinary excretion of risk is seen at levels of 2.7 mg/dL.35 However, it is not clear magnesium probably reflects magnesium intake rather whether hypermagnesemia is causal in relation to mortalthan the total body stores. ity as there are confounders (such as administration of Magnesium concentrations in tissues have been assessed as magnesium supplements for hypomagnesemia). Untanpossible measures of total body stores. Erythrocytes, monogling these will require prospective studies. Until this is cytes, sublingual epithelium, and hair cells have all been known, it seems prudent to keep magnesium levels within used for this purpose.24-27 Magnesium content in range and to be aware of the adverse outcomes associated sublingual cells correlates with the content in cardiac with both low and high magnesium concentrations. myocytes, suggesting that it is an acceptable marker for total body magnesium.24 However, a study looking at reMAGNESIUM BALANCE IN CHRONIC KIDNEY placing magnesium in CKD found that intracellular magnesium (as measured in sublingual epithelial cells) did not DISEASE increase after 8 weeks of supplementation despite increased As glomerular filtration decreases in advancing CKD, serum concentration and urinary fractional excretion of increased fractional excretion of magnesium occurs to magnesium.28 The rise in urinary magnesium in this study compensate for decreases in filtered magnesium. Nonwas not as high as the increased intestinal absorption. The diabetic patients with CKD (creatinine clearances of patients were thus in positive magnesium balance and 30-115 mL/min/1.73 m2) not on diuretics showed an inverse relationship between creatinine clearance and serum magthis presumably contributed to replacing body stores. nesium. This same relationship did not hold true for diaGiven the size of the intracellular compartment, 8 weeks was probably not long enough to see the supplemented betic patients who tended to have lower magnesium diet resulting in increased epithelial cell magnesium. levels (possibly due to decreased intestinal absorption due to autonomic neuropathy). In both groups, serum total Although there are problems with using serum magneand ionized magnesium remained in the normal range.36 sium as measure of magnesium balance, there are no other alternatives that are practical in routine clinical practice. As CKD develops beyond stage 4, there is a tendency toward hypermagnesemia, and overt hypermagnesemia is Although it will take some time for serum magnesium to frequently seen when creatinine clearance falls below deplete, a low serum concentration will usually reflect chronic negative balance. 15 mL/min.37 The degree of intestinal absorption becomes key in determining serum magnesium levels in these patients, in whom the ingestion of magnesium containing laxMAGNESIUM AND DISEASE atives or antacids can lead to hypermagnesemia.38 The use Magnesium has been linked to multiple diseases. In CKD, of phosphate binder sevelamer hydrochloride has also hypomagnesemia is associated with increased vascular Adv Chronic Kidney Dis. 2018;25(3):291-295
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been associated with hypermagnesemia in CKD.39,40 It has been postulated that this effect may be mediated by sevelamer binding to bile salts leaving more free magnesium available for absorption. There are also drugs that have the potential to cause hypomagnesemia in CKD, and the most prominent among these are PPIs. The changes in intestinal pH induced by PPIs reduce the activity of TRPM6 and can thus lead to hypomagnesemia.41 Studies have shown that patients with concomitant use of diuretics and those with kidney impairment may be at particular risk of PPI-induced hypomagnesemia.42 Hypomagnesemia resolves rapidly after discontinuation of PPIs usually within 4 days.43 Table 1 shows factors associated with both high and low magnesium levels in various CKD states.
effect describes the pull that anionic proteins exert on cations. Albumin has a slight negative charge that prevents cations such as magnesium moving across the dialyzer membrane.47 Owing to this effect, the dialysate magnesium concentration needs to be at least 3% lower than the ultrafiltrable fraction in plasma for removal to occur. Thus, hypoalbuminemic patients have relatively increased removal of magnesium on dialysis reflecting increased ionized magnesium due to less albumin binding and decreased GibbsDonnan effect. The final factor to consider is the concentration of the buffer in dialysate. High concentrations of bicarbonate will increase blood pH which increases the number of anionic sites on albumin increasing albumin binding. The decrease in ionized magnesium is reported to be 0.12 mmol/ L per pH unit.48
MAGNESIUM BALANCE IN DIALYSIS
Peritoneal Dialysis Traditional peritoneal dialysis solutions magnesium concentrations of 0.75 mmol/L are associated with hypermagnesemia.49-51 Magnesium is affected by ultrafiltration, and excretion increases with the use of hypertonic solutions.52
Hemodialysis Both ionized and total magnesium concentrations in dialysis patients tend to be above normal but remain partially dependent on the degree of residual kidney function.44 The ionized fraction of magnesium can vary between 60% and 70% in dialysis patients and increased circulating phosphate, citrate, and sulfate in kidney failure can complex magnesium and lower the ionized fraction.26 Conversely, lower albumin levels in dialysis patients could lead to a higher ionized fraction of magnesium.45 In general though, the ionized fraction of magnesium tends to be lower in dialysis patients than healthy controls.44,46 Both ionized and complexed magnesium are freely dialyzed. Dialysis patients are dependent to a large extent on the magnesium content of the dialysate to determine their magnesium balance. Mild hypermagnesemia has been reported with dialysate magnesium concentrations of 0.75 mmol/L, while concentrations of 0.5 and 0.25 mmol/L are associated with hypomagnesemia. Two factors govern the movement of ultrafiltratable magnesium between plasma and dialysate, namely the concentration gradient and the Gibbs-Donnan effect. About 70% of plasma magnesium is ultrafiltrable, the remainder being mainly albumin bound. If the dialysate concentration of magnesium is lower than the ultrafiltrable fraction concentration in plasma, magnesium will be removed in hemodialysis. The Gibbs-Donnan Table 1. Factors Associated With Increased and Decreased Serum Magnesium Concentrations in CKD Increased Magnesium Reduced GFR Drugs (sevelamer) Dialysate concentration . 0.75 mmol/L Use of magnesium supplements
Decreased Magnesium Drugs (PPIs, diuretics, calcineurin inhibitors) Hypertonic solutions (PD) Hypoalbuminemia in dialysis patients
Dialysate concentration , 0.75 mmol/L Diabetes
Abbreviations: GFR, glomerular filtration rate; PD, peritoneal dialysis; PPIs, proton-pump inhibitors.
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MAGNESIUM BALANCE IN TRANSPLANTATION Hypomagnesemia has been reported with the use of CNIs with variable incidence rates reported; 1.5-100% with a median of 60%.53-62 The incidence is generally higher with tacrolimus compared with cyclosporine.54,60,63 Transplant patients treated with CNIs have increased urinary fractional excretion magnesium (FEMg) and magnesium wasting.53,64 The mechanism is probably decreased kidney expression of epidermal growth factor (EGF) and TRPM6.53,65 EGF binds to the EGF receptor and this activates TRPM6 in the DCT.11,66,67 Tacrolimus was found to decrease expression of both the calcium channel TRPV5 and the magnesium channel TRPM6 leading to hypercalciuria and hypomagnesemia.64 A study showed that there is an inverse relationship between urinary EGF and FEMg in kidney transplant patients treated with cyclosporine.67 Magnesium balance is important after transplant for a number of reasons. Numerous studies have now linked hypomagnesemia post-transplant to post-transplant diabetes mellitus (previously new-onset diabetes after transplantation).68 There is also increasing evidence that magnesium supplementation can abrogate CNI nephrotoxicity in animal models.69 Various models have shown that magnesium prevents CNI-associated fibrosis, macrophage, and monocyte recruitment and attenuates cyclosporine-induced reduction in kidney nitric oxide production.69-71 CONCLUSION The kidneys provide the main route for magnesium excretion, and we have seen how tubular function is responsible for regulating magnesium balance in health and in mild CKD. As GFR declines, serum magnesium concentrations tend to be higher, but drugs and disease states can induce magnesium deficiency. It is also important to remember that the serum magnesium concentration represents just
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1% of total body stores. Magnesium levels in the low-normal range can therefore still be consistent with deficiency that warrants correction. Dialysis has its own unique influences on magnesium balance. Biological factors of the patient and constituents of the dialysate contribute to the transfer of magnesium during dialysis. We have also seen how magnesium is also influenced by several factors in the setting of kidney transplantation, in particular CNIs. Magnesium is increasingly recognized as a factor influencing a number of diseases that have particular relevance in chronic kidney disease. An understanding of how magnesium balance is affected across the spectrum of chronic kidney disease, dialysis, and transplantation is, therefore, of importance for all those involved in the care of these patients. REFERENCES 1. 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. 2. Laecke SV, Nagler EV, Verbeke F, Biesen WV, Vanholder R. Hypomagnesemia and the risk of death and GFR decline in chronic kidney disease. Am J Med. 2013;126:825-831. 3. Hashimoto T, Hara A, Ohkubo T, et al. Serum magnesium, ambulatory blood pressure, and carotid artery alteration: the Ohasama study. Am J Hypertens. 2010;23:1292-1298. 4. Graham LA, Caesar JJ, Burgen AS. Gastrointestinal absorption and excretion of Mg 28 in man. Metabolism. 1960;9:646-659. 5. Fine KD, Santa Ana CA, Porter JL, Fordtran JS. Intestinal absorption of magnesium from food and supplements. J Clin Invest. 1991;88:396-402. 6. Quamme GA. Recent developments in intestinal magnesium absorption. Curr Opin Gastroenterol. 2008;24:230-235. 7. Schmulen AC, Lerman M, Pak CY, et al. Effect of 1,25-(OH)2D3 on jejunal absorption of magnesium in patients with chronic renal disease. Am J Physiol. 1980;238:G349-G352. 8. Hardwick LL, Jones MR, Brautbar N, Lee DB. Magnesium absorption: mechanisms and the influence of vitamin D, calcium and phosphate. J Nutr. 1991;121(1):13-23. 9. Groenestege WMT, Hoenderop JG, Heuvel L, van den, Knoers N, Bindels RJ. The epithelial Mg21 channel transient receptor potential melastatin 6 is regulated by dietary Mg21 content and estrogens. J Am Soc Nephrol. 2006;17:1035-1043. 10. Karbach U. Magnesium transport across colon ascendens of the rat. Dig Dis Sci. 1989;34:1825-1831. 11. Groenestege WMT, Thebault S, van der Wijst J, et al. Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia. J Clin Invest. 2007;117:2260-2267. 12. Elisaf M, Panteli K, Theodorou J, Siamopoulos KC. Fractional excretion of magnesium in normal subjects and in patients with hypomagnesemia. Magnes Res. 1997;10:315-320. 13. Quamme GA, Dirks JH. Intraluminal and contraluminal magnesium on magnesium and calcium transfer in the rat nephron. Am J Physiol. 1980;238:F187-F198. 14. Chang W, Pratt S, Chen TH, Nemeth E, Huang Z, Shoback D. Coupling of calcium receptors to inositol phosphate and cyclic AMP generation in mammalian cells and Xenopus laevis oocytes and immunodetection of receptor protein by region-specific antipeptide antisera. J Bone Miner Res. 1998;13:570-580. 15. Bapty BW, Dai LJ, Ritchie G, Canaff L, Hendy GN, Quamme GA. Extracellular Mg2(1)- and Ca2(1)-sensing in mouse distal convoluted tubule cells. Kidney Int. 1998;53:583-592.
16. Estep H, Shaw WA, Watlington C, Hobe R, Holland W, Tucker SG. Hypocalcemia due to hypomagnesemia and reversible parathyroid hormone unresponsiveness. J Clin Endocrinol Metab. 1969;29:842-848. 17. Rude RK, Baker AJ. Renal cortical adenylate cyclase: characterization of magnesium activation. Endocrinology. 1983;113:1348-1355. 18. Ikari A, Sanada A, Okude C, et al. Up-regulation of TRPM6 transcriptional activity by AP-1 in renal epithelial cells. J Cell Physiol. 2010;222:481-487. 19. Cao G, van der Wijst J, van der Kemp A, van Zeeland F, Bindels RJ, Hoenderop JG. Regulation of the epithelial Mg21 channel TRPM6 by estrogen and the associated repressor protein of estrogen receptor activity (REA). J Biol Chem. 2009;284:14788-14795. 20. Nielsen FH, Johnson LAK. Data from controlled metabolic ward studies provide guidance for the determination of status indicators and dietary requirements for magnesium. Biol Trace Elem Res. 2017;177:43-52. 21. 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) Study123. Am J Clin Nutr. 2014;100:756-764. 22. Del Gobbo LC, Imamura F, Wu JH, de Oliveira Otto MC, Chiuve SE, 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. 23. 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. 24. Haigney MCP, Silver B, Tanglao E, et al. Noninvasive measurement of tissue magnesium and correlation with cardiac levels. Circulation. 1995;92:2190-2197. 25. Walser M. Magnesium metabolism. Ergeb Physiol. 1967;59:185-296. 26. Huijgen HJ, van Ingen HE, Kok WT, Sanders GT. Magnesium fractions in serum of healthy individuals and CAPD patients, measured by an ion-selective electrode and ultrafiltration. Clin Biochem. 1996;29:261-266. 27. Długaszek M, Szopa M, Rzeszotarski J, Karbowiak P. Magnesium, calcium and trace elements distribution in serum, erythrocytes, and hair of patients with chronic renal failure. Magnes Res. 2008;21:109-117. 28. Bressendorff I, Hansen D, Schou M, et al. Oral magnesium supplementation in chronic kidney disease stages 3 and 4: efficacy, safety, and effect on serum calcification propensity—a prospective randomized double-blinded placebo-controlled clinical trial. Kidney Int Rep. 2017;2:380-389. 29. Villa-Bellosta R, Millan A, Sorribas V. Role of calcium-phosphate deposition in vascular smooth muscle cell calcification. Am J Physiol Cell Physiol. 2011;300:C210-C220. 30. 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. 31. Louvet L, Metzinger L, B€ uchel J, Steppan S, Massy ZA. 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. 32. Ivanovski O, Nikolov IG, Joki N, et al. The calcimimetic R-568 retards uremia-enhanced vascular calcification and atherosclerosis in apolipoprotein E deficient (apoE2/2) mice. Atherosclerosis. 2009;205:55-62. 33. Lacson E, Wang W, Ma L, Passlick-Deetjen J. Serum magnesium and mortality in hemodialysis patients in the United States: a cohort study. Am J Kidney Dis. 2015;66:1056-1066. 34. Cheungpasitporn W, Thongprayoon C, Qian Q. Dysmagnesemia in hospitalized patients: prevalence and prognostic importance. Mayo Clin Proc. 2015;90:1001-1010.
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35. Sakaguchi Y, Fujii N, Shoji T, Hayashi T, Rakugi H, Isaka Y. Hypomagnesemia is a significant predictor of cardiovascular and non-cardiovascular mortality in patients undergoing hemodialysis. Kidney Int. 2014;85:174-181. 36. Dewitte K, Dhondt A, Giri M, et al. Differences in serum ionized and total magnesium values during chronic renal failure between nondiabetic and diabetic patients. Diabetes Care. 2004;27:2503-2505. 37. Coburn JW, Popovtzer MM, Massry SG, Kleeman CR. The physicochemical state and renal handling of divalent ions in chronic renal failure. Arch Intern Med. 1969;124:302-311. 38. Schelling JR. Fatal hypermagnesemia. Clin Nephrol. 2000;53:61-65. 39. Mitsopoulos E, Griveas I, Zanos S, et al. Increase in serum magnesium level in Haemodialysis patients receiving sevelamer hydrochloride. Int Urol Nephrol. 2005;37:321-328. 40. Rosa-Diez G, Negri AL, Crucelegui MS, et al. Sevelamer carbonate reduces the risk of hypomagnesemia in hemodialysis-requiring end-stage renal disease patients. Clin Kidney J. 2016;9:481-485. 41. Bai JPF, 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. 42. Sumukadas D, Habicht D, McMurdo MET. Proton pump inhibitors are associated with lower magnesium levels in older people with chronic kidney disease. J Am Geriatr Soc. 2012;60:392-393. 43. Hess MW, Hoenderop JGJ, Bindels RJM, Drenth JPH. Systematic review: hypomagnesaemia induced by proton pump inhibition. Aliment Pharmacol Ther. 2012;36:405-413. 44. Saha HH, Harmoinen AP, Pasternack AI. Measurement of serum ionized magnesium in CAPD patients. Perit Dial Int. 1997;17:347-352. 45. Saha H, Harmoinen A, Karvonen AL, Mustonen J, Pasternack A. Serum ionized versus total magnesium in patients with intestinal or liver disease. Clin Chem Lab Med. 1998;36:715-718. 46. Truttmann AC, Faraone R, Von Vigier RO, Nuoffer JM, Pfister R, Bianchetti MG. Maintenance hemodialysis and circulating ionized magnesium. Nephron. 2002;92:616-621. 47. Rippe B, Venturoli D. Optimum electrolyte composition of a dialysis solution. Perit Dial Int J Int Soc Perit Dial. 2008;28(Suppl 3):S131-S136. 48. Wang S, McDonnell EH, Sedor FA, Toffaletti JG. pH effects on measurements of ionized calcium and ionized magnesium in blood. Arch Pathol Lab Med. 2002;126:947-950. 49. Hutchison AJ, Merchant M, Boulton HF, Hinchcliffe R, Gokal R. Calcium and magnesium mass transfer in peritoneal dialysis patients using 1.25 mmol/L calcium, 0.25 mmol/L magnesium dialysis fluid. Perit Dial Int J Int Soc Perit Dial. 1993;13:219-223. 50. Blumenkrantz MJ, Kopple JD, Moran JK, Coburn JW. Metabolic balance studies and dietary protein requirements in patients undergoing continuous ambulatory peritoneal dialysis. Kidney Int. 1982;21:849-861. 51. Katopodis KP, Koliousi EL, Andrikos EK, Pappas MV, Elisaf MS, Siamopoulos KC. Magnesium homeostasis in patients undergoing continuous ambulatory peritoneal dialysis: role of the dialysate magnesium concentration. Artif Organs. 2003;27:853-857. 52. Kwong MBL, Lee JSK, Chan MK. Transperitoneal calcium and magnesium transfer during an 8-Hour dialysis. Periton Dial Bull. 1987;7:85-89. 53. Barton CH, Vaziri ND, Martin DC, Choi S, Alikhani S. Hypomagnesemia and renal magnesium wasting in renal transplant recipients receiving cyclosporine. Am J Med. 1987;83:693-699.
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54. Margreiter R. Efficacy and safety of tacrolimus compared with ciclosporin microemulsion in renal transplantation: a randomised multicentre study. Lancet. 2002;359:741-746. 55. Thompson C, Sullivan K, June C, Thomas ED. Association between cyclosporin neurotoxicity and hypomagnesaemia. Lancet. 1984;324:1116-1120. 56. Cavdar C, Sifil A, Sanli E, G€ ulay H, Camsari T. Hypomagnesemia and mild rhabdomyolysis in living related donor renal transplant recipient treated with cyclosporine A. Scand J Urol Nephrol. 1998;32:415-417. 57. Bernstein L, Levin R. Catatonia responsive to intravenous lorazepam in a patient with cyclosporine neurotoxicity and hypomagnesemia. Psychosomatics. 1993;34:102-103. 58. June CH, Thompson CB, Kennedy MS, Loughran TP, Deeg HJ. Correlation of hypomagnesemia with the onset of cyclosporineassociated hypertension in marrow transplant patients. Transplantation. 1986;41:47-51. 59. al-Khursany I, Thomas TH, Harrison K, Wilkinson R. Reduced erythrocyte and leukocyte magnesium is associated with cyclosporin treatment and hypertension in renal transplant patients. Nephrol Dial Transplant. 1992;7:251-255. 60. Trompeter R, Filler G, Webb NJ, et al. Randomized trial of tacrolimus versus cyclosporin microemulsion in renal transplantation. Pediatr Nephrol Berl Ger. 2002;17:141-149. 61. Scoble JE, Freestone A, Varghese Z, et al. Cyclosporin-induced renal magnesium leak in renal transplant patients. Nephrol Dial Transplant. 1990;5:812-815. 62. Ryffel B, Weber E, Mihatsch MJ. Nephrotoxicity of immunosuppressants in rats: comparison of macrolides with cyclosporin. Exp Nephrol. 1994;2:324-333. 63. Arthur JM, Shamim S. Interaction of cyclosporine and FK506 with diuretics in transplant patients. Kidney Int. 2000;58:325-330. 64. Nijenhuis T, Hoenderop JGJ, Bindels RJM. Downregulation of Ca21 and Mg21 transport proteins in the kidney explains tacrolimus (FK506)-induced hypercalciuria and hypomagnesemia. J Am Soc Nephrol. 2004;15:549-557. 65. Baaij JHF, de, Hoenderop JGJ, Bindels RJM. Magnesium in man: implications for health and disease. Physiol Rev. 2015;95:1-46. 66. Thebault S, Alexander RT, Groenestege WMT, Hoenderop JG, Bindels RJ. EGF increases TRPM6 activity and surface expression. J Am Soc Nephrol. 2009;20:78-85. 67. Ledeganck KJ, De Winter BY, Van den Driessche A, et al. Magnesium loss in cyclosporine-treated patients is related to renal epidermal growth factor downregulation. Nephrol Dial Transplant. 2014;29:1097-1102. 68. Cheungpasitporn W, Thongprayoon C, Harindhanavudhi T, Edmonds PJ, Erickson SB. Hypomagnesemia linked to new-onset diabetes mellitus after kidney transplantation: a systematic review and meta-analysis. Endocr Res. 2016;41:142-147. 69. Asai T, Nakatani T, Yamanaka S, et al. Magnesium supplementation prevents experimental chronic cyclosporine a nephrotoxicity via renin-angiotensin system independent mechanism. Transplantation. 2002;74:784-791. 70. Rob PM, Lebeau A, Nobiling R, et al. Magnesium metabolism: basic aspects and implications of ciclosporine toxicity in rats. Nephron. 1996;72:59-66. 71. Yuan J, Zhou J, Chen BC, et al. Magnesium supplementation prevents chronic cyclosporine nephrotoxicity via adjusting nitric oxide synthase activity. Transplant Proc. 2005;37:1892-1895.
Magnesium Balance in Chronic and End-Stage Kidney Disease Ben Oliveira, John Cunningham, and Stephen B. Walsh This article explores the effects of CKD and end-stage kidney disease on magnesium balance. In CKD, there is decreased glomerular filtration of magnesium. Decreased tubular reabsorption can compensate to a degree, but once CKD stage 4 is reached there is a tendency toward hypermagnesemia. In dialysis, magnesium balance is dependent on the constituents of the dialysate that the blood is exposed to. The concentration of dialysate magnesium is just one of the factors that need to be considered. During transplantation, there are particular effects of immunosuppressants that can affect the magnesium balance and need to be considered by the clinician. Q 2018 by the National Kidney Foundation, Inc. All rights reserved. Key Words: Electrolytes, Magnesium, Kidney disease
INTRODUCTION Magnesium is the eighth most abundant element within the earth’s crust, the second most prevalent intracellular cation after potassium, is crucial for the functioning of ATP as well as the synthesis of both DNA and RNA, and is a cofactor in over 300 enzymatic reactions. Important links exist between this alkali earth metal and vascular calcification, cardiovascular disease, and CKD development.1-3 Magnesium balance is regulated via absorption from the gastrointestinal tract and elimination by the kidneys. The kidney excretion of magnesium depends on the glomerular filtration rate (GFR) that is then modulated by tubular reabsorption. As the GFR falls, the kidney’s ability to excrete magnesium declines, and thus, there is a tendency for hypermagnesemia in CKD. However, there are other factors that contribute to magnesium balance in CKD, such as drugs (e.g. proton-pump inhibitors [PPIs], calcineurin inhibitors [CNIs]), vitamin D status, and the presence of diabetes. For patients on dialysis, magnesium excretion depends largely on the magnesium gradient across the dialysis membrane and other factors related to the patient and dialysate. NORMAL MAGNESIUM BALANCE To understand magnesium dysregulation in CKD, it is necessary briefly to touch on magnesium homeostasis in health. Extracellular magnesium accounts for 1% of total body magnesium with most of the remaining 99% sequestered in bones and muscles. Magnesium is absorbed in the gut and predominantly excreted by the kidneys. The fractional absorption of dietary magnesium is typically around 30%, and this can increase and decrease in response to both low and high magnesium diets, respectively.4,5 Two transport mechanisms have been defined for intestinal magnesium absorption: paracellular and transcellular routes. Paracellular transport accounts for 80-90% of total absorption and is a passive process driven by the relatively high luminal concentration of magnesium and the electropositive transluminal gradient.6 Transcellular magnesium relies on transport through the transient receptor potential channel melastatin member 6 (TRPM6) and TRPM7 channels.6 Intestinal absorption may be influenced by vitamin D status7,8 but Adv Chronic Kidney Dis. 2018;25(3):291-295
this is controversial9,10 and kidney TRPM6 expression per se does not appear to be influenced by vitamin D.11 The main excretory pathway for magnesium is kidney where the fractional excretion can change from nearly 0.5% in hypomagnesemia to greater than 70% in hypermagnesemia.12 Magnesium is freely filtered (70-80% of magnesium is ultrafiltratable, the rest is protein bound) at the glomerulus, but under normal circumstances, approximately 95% is reabsorbed along the course of the kidney tubule. Bulk magnesium transport (up to 70%) occurs in the thick ascending limb with passive paracellular magnesium uptake. This process is driven by the luminal positive gradient driven by K1 recycling via apical NKCC2 and ROMK transporters in thick ascending limb cells. The tight junction proteins claudin-16 and claudin19 comprise the paracellular route for magnesium reabsorption driven by this gradient. Fine-tuning of magnesium reabsorption occurs in the distal convoluted tubule (DCT) and is an active process driven by TRPM6. The magnesium extruding transport protein on the basolateral cell membrane has yet to be identified. Regulation of kidney magnesium handling in the DCT is partly under control of parathyroid hormone (PTH) which increases tubular reabsorption of the cation.13 Hypomagnesemia stimulates PTH synthesis and release via the calcium sensing receptor (CaSR) in the parathyroid glands, though with potency 2 to 3 times less than that of calcium.14 However, in the DCT, the potency of magnesium and calcium as activators of the CaSR appears equal.15 In the parathyroids, the CaSR exhibits a biphasic response in that very low levels of magnesium can reduce the sensitivity of the CaSR to calcium, as well as to magnesium itself, leading to decreased PTH release and profound hypocalcemia, a scenario that requires correction of the hypomagnesemia to restore the responsiveness of the CaSR to calcium and From the Centre for Nephrology, Royal Free Hospital, London, UK. Financial Disclosure: The authors declare that they have no relevant financial interests. Address correspondence to Ben Oliveira, North Middlesex University Hospital, Renal Medicine, London N181QX, UK. E-mail: [email protected] Ó 2018 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 https://doi.org/10.1053/j.ackd.2018.01.004
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allow appropriate release of PTH.16 PTH secretion is mediated by cyclic adenosine monophosphate. Cyclic adenosine monophosphate is dependent on magnesium for its production and this explains the unresponsiveness of the parathyroids in profound hypomagnesemia.17 Other players involved in magnesium regulation in the DCT include epidermal growth factor and estrogen which activate transcription of TRPM6.18,19
calcification and mortality. The pathogenesis of vascular calcification in kidney disease is complicated and beyond the scope of this article. In brief, calcium phosphate can influence vascular smooth muscle cells (VSMCs) to become osteoblast like, promoting vascular calcification.29 It has been shown that in vitro magnesium is able to prevent this process from occurring. In vitro studies have shown that magnesium inhibits osteogenic transformation and calcification of VSMCs, which is probably mediated via ASSESSING MAGNESIUM STATUS TRPM7 channels.30 It also modulates the expression of several anticalcification proteins possibly via restoring miAlthough the usual starting point is measurement of blood magnesium concentration, this compartment only consticroRNA signature at the site of calcification.30,31 Magnesium can also activate the CaSR found in VSMCs, tutes about 1% of the body’s total stores. A person in negative and this has also been shown to attenuate vascular magnesium balance will mobilize stores in muscle and bone calcification.32 Hypomagnesemia can, therefore, lead to to maintain serum levels. Thus, total magnesium stores have increased vascular calcification which will increase cardioto be quite low before this is reflected by the serum concentravascular risk burden. Indeed tion. Indeed, healthy volunstudies have shown that low teers on magnesium deficient CLINICAL SUMMARY magnesium levels are associdiets did not deplete their ated with death in dialysis serum levels after 92 days.20 There is a tendency toward hypermagnesemia in CKD. patients.33 There is also evidence that Constituents of the diasylate are the main factors governing A J-shaped curve describes those with serum levels in magnesium status in dialysis patients. the relationship between the the low-normal range (0.75– serum magnesium and mor0.80 mmol/L) may be func In transplantation, calcineurin inhibitors can lead to tality. An observational tionally magnesium deficient hypomagnesemia. study of over 65,000 patients as they display increased found that a magnesium chronic disease risk akin to level above 2.3 mg/dL was a predictor of adverse outthose with levels less than 0.75 mmol/L.21-23. Urinary excretion is modified within a few days of a change in comes.34 A similar relationship is seen in dialysis patients, 20 but in contrast to the previous study, the lowest level of gastrointestinal absorption. Thus, the urinary excretion of risk is seen at levels of 2.7 mg/dL.35 However, it is not clear magnesium probably reflects magnesium intake rather whether hypermagnesemia is causal in relation to mortalthan the total body stores. ity as there are confounders (such as administration of Magnesium concentrations in tissues have been assessed as magnesium supplements for hypomagnesemia). Untanpossible measures of total body stores. Erythrocytes, monogling these will require prospective studies. Until this is cytes, sublingual epithelium, and hair cells have all been known, it seems prudent to keep magnesium levels within used for this purpose.24-27 Magnesium content in range and to be aware of the adverse outcomes associated sublingual cells correlates with the content in cardiac with both low and high magnesium concentrations. myocytes, suggesting that it is an acceptable marker for total body magnesium.24 However, a study looking at reMAGNESIUM BALANCE IN CHRONIC KIDNEY placing magnesium in CKD found that intracellular magnesium (as measured in sublingual epithelial cells) did not DISEASE increase after 8 weeks of supplementation despite increased As glomerular filtration decreases in advancing CKD, serum concentration and urinary fractional excretion of increased fractional excretion of magnesium occurs to magnesium.28 The rise in urinary magnesium in this study compensate for decreases in filtered magnesium. Nonwas not as high as the increased intestinal absorption. The diabetic patients with CKD (creatinine clearances of patients were thus in positive magnesium balance and 30-115 mL/min/1.73 m2) not on diuretics showed an inverse relationship between creatinine clearance and serum magthis presumably contributed to replacing body stores. nesium. This same relationship did not hold true for diaGiven the size of the intracellular compartment, 8 weeks was probably not long enough to see the supplemented betic patients who tended to have lower magnesium diet resulting in increased epithelial cell magnesium. levels (possibly due to decreased intestinal absorption due to autonomic neuropathy). In both groups, serum total Although there are problems with using serum magneand ionized magnesium remained in the normal range.36 sium as measure of magnesium balance, there are no other alternatives that are practical in routine clinical practice. As CKD develops beyond stage 4, there is a tendency toward hypermagnesemia, and overt hypermagnesemia is Although it will take some time for serum magnesium to frequently seen when creatinine clearance falls below deplete, a low serum concentration will usually reflect chronic negative balance. 15 mL/min.37 The degree of intestinal absorption becomes key in determining serum magnesium levels in these patients, in whom the ingestion of magnesium containing laxMAGNESIUM AND DISEASE atives or antacids can lead to hypermagnesemia.38 The use Magnesium has been linked to multiple diseases. In CKD, of phosphate binder sevelamer hydrochloride has also hypomagnesemia is associated with increased vascular Adv Chronic Kidney Dis. 2018;25(3):291-295
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been associated with hypermagnesemia in CKD.39,40 It has been postulated that this effect may be mediated by sevelamer binding to bile salts leaving more free magnesium available for absorption. There are also drugs that have the potential to cause hypomagnesemia in CKD, and the most prominent among these are PPIs. The changes in intestinal pH induced by PPIs reduce the activity of TRPM6 and can thus lead to hypomagnesemia.41 Studies have shown that patients with concomitant use of diuretics and those with kidney impairment may be at particular risk of PPI-induced hypomagnesemia.42 Hypomagnesemia resolves rapidly after discontinuation of PPIs usually within 4 days.43 Table 1 shows factors associated with both high and low magnesium levels in various CKD states.
effect describes the pull that anionic proteins exert on cations. Albumin has a slight negative charge that prevents cations such as magnesium moving across the dialyzer membrane.47 Owing to this effect, the dialysate magnesium concentration needs to be at least 3% lower than the ultrafiltrable fraction in plasma for removal to occur. Thus, hypoalbuminemic patients have relatively increased removal of magnesium on dialysis reflecting increased ionized magnesium due to less albumin binding and decreased GibbsDonnan effect. The final factor to consider is the concentration of the buffer in dialysate. High concentrations of bicarbonate will increase blood pH which increases the number of anionic sites on albumin increasing albumin binding. The decrease in ionized magnesium is reported to be 0.12 mmol/ L per pH unit.48
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Peritoneal Dialysis Traditional peritoneal dialysis solutions magnesium concentrations of 0.75 mmol/L are associated with hypermagnesemia.49-51 Magnesium is affected by ultrafiltration, and excretion increases with the use of hypertonic solutions.52
Hemodialysis Both ionized and total magnesium concentrations in dialysis patients tend to be above normal but remain partially dependent on the degree of residual kidney function.44 The ionized fraction of magnesium can vary between 60% and 70% in dialysis patients and increased circulating phosphate, citrate, and sulfate in kidney failure can complex magnesium and lower the ionized fraction.26 Conversely, lower albumin levels in dialysis patients could lead to a higher ionized fraction of magnesium.45 In general though, the ionized fraction of magnesium tends to be lower in dialysis patients than healthy controls.44,46 Both ionized and complexed magnesium are freely dialyzed. Dialysis patients are dependent to a large extent on the magnesium content of the dialysate to determine their magnesium balance. Mild hypermagnesemia has been reported with dialysate magnesium concentrations of 0.75 mmol/L, while concentrations of 0.5 and 0.25 mmol/L are associated with hypomagnesemia. Two factors govern the movement of ultrafiltratable magnesium between plasma and dialysate, namely the concentration gradient and the Gibbs-Donnan effect. About 70% of plasma magnesium is ultrafiltrable, the remainder being mainly albumin bound. If the dialysate concentration of magnesium is lower than the ultrafiltrable fraction concentration in plasma, magnesium will be removed in hemodialysis. The Gibbs-Donnan Table 1. Factors Associated With Increased and Decreased Serum Magnesium Concentrations in CKD Increased Magnesium Reduced GFR Drugs (sevelamer) Dialysate concentration . 0.75 mmol/L Use of magnesium supplements
Decreased Magnesium Drugs (PPIs, diuretics, calcineurin inhibitors) Hypertonic solutions (PD) Hypoalbuminemia in dialysis patients
Dialysate concentration , 0.75 mmol/L Diabetes
Abbreviations: GFR, glomerular filtration rate; PD, peritoneal dialysis; PPIs, proton-pump inhibitors.
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MAGNESIUM BALANCE IN TRANSPLANTATION Hypomagnesemia has been reported with the use of CNIs with variable incidence rates reported; 1.5-100% with a median of 60%.53-62 The incidence is generally higher with tacrolimus compared with cyclosporine.54,60,63 Transplant patients treated with CNIs have increased urinary fractional excretion magnesium (FEMg) and magnesium wasting.53,64 The mechanism is probably decreased kidney expression of epidermal growth factor (EGF) and TRPM6.53,65 EGF binds to the EGF receptor and this activates TRPM6 in the DCT.11,66,67 Tacrolimus was found to decrease expression of both the calcium channel TRPV5 and the magnesium channel TRPM6 leading to hypercalciuria and hypomagnesemia.64 A study showed that there is an inverse relationship between urinary EGF and FEMg in kidney transplant patients treated with cyclosporine.67 Magnesium balance is important after transplant for a number of reasons. Numerous studies have now linked hypomagnesemia post-transplant to post-transplant diabetes mellitus (previously new-onset diabetes after transplantation).68 There is also increasing evidence that magnesium supplementation can abrogate CNI nephrotoxicity in animal models.69 Various models have shown that magnesium prevents CNI-associated fibrosis, macrophage, and monocyte recruitment and attenuates cyclosporine-induced reduction in kidney nitric oxide production.69-71 CONCLUSION The kidneys provide the main route for magnesium excretion, and we have seen how tubular function is responsible for regulating magnesium balance in health and in mild CKD. As GFR declines, serum magnesium concentrations tend to be higher, but drugs and disease states can induce magnesium deficiency. It is also important to remember that the serum magnesium concentration represents just
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1% of total body stores. Magnesium levels in the low-normal range can therefore still be consistent with deficiency that warrants correction. Dialysis has its own unique influences on magnesium balance. Biological factors of the patient and constituents of the dialysate contribute to the transfer of magnesium during dialysis. We have also seen how magnesium is also influenced by several factors in the setting of kidney transplantation, in particular CNIs. Magnesium is increasingly recognized as a factor influencing a number of diseases that have particular relevance in chronic kidney disease. An understanding of how magnesium balance is affected across the spectrum of chronic kidney disease, dialysis, and transplantation is, therefore, of importance for all those involved in the care of these patients. REFERENCES 1. 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. 2. Laecke SV, Nagler EV, Verbeke F, Biesen WV, Vanholder R. Hypomagnesemia and the risk of death and GFR decline in chronic kidney disease. Am J Med. 2013;126:825-831. 3. Hashimoto T, Hara A, Ohkubo T, et al. Serum magnesium, ambulatory blood pressure, and carotid artery alteration: the Ohasama study. Am J Hypertens. 2010;23:1292-1298. 4. Graham LA, Caesar JJ, Burgen AS. Gastrointestinal absorption and excretion of Mg 28 in man. Metabolism. 1960;9:646-659. 5. Fine KD, Santa Ana CA, Porter JL, Fordtran JS. Intestinal absorption of magnesium from food and supplements. J Clin Invest. 1991;88:396-402. 6. Quamme GA. Recent developments in intestinal magnesium absorption. Curr Opin Gastroenterol. 2008;24:230-235. 7. Schmulen AC, Lerman M, Pak CY, et al. Effect of 1,25-(OH)2D3 on jejunal absorption of magnesium in patients with chronic renal disease. Am J Physiol. 1980;238:G349-G352. 8. Hardwick LL, Jones MR, Brautbar N, Lee DB. Magnesium absorption: mechanisms and the influence of vitamin D, calcium and phosphate. J Nutr. 1991;121(1):13-23. 9. Groenestege WMT, Hoenderop JG, Heuvel L, van den, Knoers N, Bindels RJ. The epithelial Mg21 channel transient receptor potential melastatin 6 is regulated by dietary Mg21 content and estrogens. J Am Soc Nephrol. 2006;17:1035-1043. 10. Karbach U. Magnesium transport across colon ascendens of the rat. Dig Dis Sci. 1989;34:1825-1831. 11. Groenestege WMT, Thebault S, van der Wijst J, et al. Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia. J Clin Invest. 2007;117:2260-2267. 12. Elisaf M, Panteli K, Theodorou J, Siamopoulos KC. Fractional excretion of magnesium in normal subjects and in patients with hypomagnesemia. Magnes Res. 1997;10:315-320. 13. Quamme GA, Dirks JH. Intraluminal and contraluminal magnesium on magnesium and calcium transfer in the rat nephron. Am J Physiol. 1980;238:F187-F198. 14. Chang W, Pratt S, Chen TH, Nemeth E, Huang Z, Shoback D. Coupling of calcium receptors to inositol phosphate and cyclic AMP generation in mammalian cells and Xenopus laevis oocytes and immunodetection of receptor protein by region-specific antipeptide antisera. J Bone Miner Res. 1998;13:570-580. 15. Bapty BW, Dai LJ, Ritchie G, Canaff L, Hendy GN, Quamme GA. Extracellular Mg2(1)- and Ca2(1)-sensing in mouse distal convoluted tubule cells. Kidney Int. 1998;53:583-592.
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