What’s Up with Magnesium in Patients With CKD?

From the Chair

Like many in practice, I have not paid much attention to the serum magnesium (Mg) in patients with chronic kidney disease (CKD)—usually not checking the Mg level unless the patient is hypokalemic on a diuretic or has underlying cardiac disease, or in an acute setting when there might be evidence of ventricular dysrhythmias. However, over the past few years, there has been a spate of articles on the association between serum magnesium, high or low, and adverse outcomes in patients with CKD. Should we be paying more attention to Mg?

Mg is a divalent ion that is mostly stored in bone or intracellularly (>99%). The serum Mg accounts for about 0.3% of total-body Mg. A normal Mg level is in the 1.3-2.0 mEq/L (1.6-2.4 mg/dl) range. Excretion of Mg occurs mostly via the gastrointestinal tract (70%). Of the 30% of Mg that is excreted by the kidneys, 30% is reabsorbed by the proximal tubule and the remainder is handled more distally: 70% reabsorbed in the thick ascending limb, and 10%-15% handled via a Mg channel, the melastatin-related transient receptor potential cation channel 6 (TRPM6) in the distal convoluted tubule.¹

A typical diet contains approximately 360 mg magnesium, and three-quarters is excreted in the feces. Normal kidneys excrete about 100 mg magnesium per day. A low Mg is relatively common in CKD patients—a prevalence rate of about 15% even in CKD stages G4 and G5,^1,2 especially among proteinuric patients,² or if they are being treated with high doses of diuretics or with a proton pump inhibitor (PPI). In ESRD patients, a modestly elevated Mg level may be seen but its significance has been unclear and may depend on dialysis clearance.³

The evidence of an association between Mg and cardiovascular outcomes in CKD patients is quite tenuous. In the best study so far, an observational analysis of the CRIC dataset,⁴  Negrea and colleagues suggest a U-shaped association between Mg <1.9 mg/dL and Mg >2.1 mg/dL and cardiovascular outcomes. However, the association was observed only in crude models and became statistically nonsignificant in models adjusted for demographic, laboratory, and clinical factors. Hardly very convincing. In an accompanying editorial,⁵ Kula and Bansal agree. Both Negrea et al and Kula et al acknowledge the many limitations of the study using the CRIC dataset, including the limitations of having only one Mg measurement, the limitation of serum Mg in estimating total-body Mg stores, and the almost universal criticism of any observational study, namely residual confounding.

Hypomagnesemia has also been studied as a risk factor for renal progression. Sakaguchi has suggested hypomagnesemia to be a predictor of progression to ESRD in diabetic nephropathy.⁷ In one study, a retrospective analysis, hypomagnesemia increased the risk of phosphate-induced renal injury.⁸ The possibility that hypomagnesemia enhances (and Mg administration might prevent) calcium-phosphate crystal formation within the proximal tubular lumen has been invoked. The hypothesis being that CaxPhos crystals cause damage to the tubular epithelium and thus induce interstitial fibrosis.⁹ Still, my review of the studies published so far indicates a connection between Mg and renal fibrosis that is unproven.

Mg in preventing vascular calcification has also been suggested in the literature.² While the inhibition of calcium phosphate crystal formation by Mg, both in vitro and in animal models, has been reported,² reducing cardiovascular complications or reducing mortality by treating CKD patients with Mg has not been convincingly demonstrated.²

Treatment with a thiazide diuretic has been associated with hypomagnesemia. In a small double-blind randomized trial, Odvina et al¹⁰ reported higher rates of hypomagnesemia in thiazide-treated patients that could be prevented by K-Mg-citrate treatment. The diuretic-induced magnesium deficiency influences potassium metabolism. Magnesium is a necessary activator of Na-K-ATPase, which supplies the Na-K pump with energy.¹¹ Lack of magnesium will therefore impair the pumping of sodium out of the cell and of potassium into the cell.

So, my take on the relationship between Mg and clinical outcomes is that the jury is still out. Should we check serum Mg in CKD patients? Checking Mg could be worthwhile, especially in hypokalemic patients with CKD who are receiving aggressive diuretic therapy with either thiazide or loop diuretics. This is because correcting hypomagnesemia might allow for the successful treatment of hypokalemia. Monitoring the Mg level and correcting as necessary would also be reasonable in CKD patients with ischemic heart disease, especially where there is a concern about arrhythmias. But I do not think we are at a stage where we should be monitoring Mg in all our CKD patients on a regular basis.

REFERENCES

1. Curry JN, Yu ASL. Magnesium handling in the kidney. Adv Chronic Kidney Dis. 2018;25(3):236-243. doi:10.1053/j.ackd.2018.01.003. PMID:29793662; PMCID:PMC6932629.
2. Sakaguchi Y. The emerging role of magnesium in CKD. Clin Exp Nephrol. 2022;26(5):379-384. doi:10.1007/s10157-022-02182-4. PMID:35076791; PMCID:PMC9012765.
3. Oka T, Hamano T, Sakaguchi Y, et al. Proteinuria-associated renal magnesium wasting leads to hypomagnesemia: a common electrolyte abnormality in chronic kidney disease. Nephrol Dial Transplant. 2019;34:1154-1162. doi:10.1093/ndt/gfy119.
4. Pun PH, Middleton JP. Dialysate potassium, dialysate magnesium, and hemodialysis risk. J Am Soc Nephrol. 2017;28(12):3441-3451.
5. Negrea L, DeLozier SJ, Janes JL. Serum magnesium and cardiovascular outcomes and mortality in CKD: the Chronic Renal Insufficiency Cohort (CRIC). Kidney Med. 2021;3(2):183-192.
6. Kula AJ, Bansal N. Magnesium and cardiovascular disease in CKD: the mysteries of a humble divalent cation. Kidney Med. 2021;3(2):162-164. doi:10.1016/j.xkme.2021.02.002. PMID:33851109; PMCID:PMC8039415.
7. 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. doi:10.2337/dc12-0226.
8. 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. doi:10.1038/ki.2015.165.
9. Shiizaki K, Tsubouchi A, Miura Y, et al. Calcium phosphate microcrystals in the renal tubular fluid accelerate chronic kidney disease progression. J Clin Invest. 2021;131:145693. doi:10.1172/JCI145693.
10. Odvina CV, Mason RP, Pak CY. Prevention of thiazide-induced hypokalemia without magnesium depletion by potassium-magnesium-citrate. Am J Ther. 2006;13(2):101-108. doi:10.1097/01.mjt.0000149922.16098.c0. PMID:16645424.
11. Wester PO, Dyckner T. Problems with potassium and magnesium in diuretic-treated patients. Acta Pharmacol Toxicol (Copenh). 1984;54 Suppl 1:59-65. doi:10.1111/j.1600-0773.1984.tb03634.x. PMID:6324542.