Physiology of a Forgotten Electrolyte—Magnesium Disorders

Abstract

Magnesium (Mg²⁺) is the second most common intracellular cation and the fourth most abundant element on earth. However, Mg²⁺ is a frequently overlooked electrolyte and often not measured in patients. While hypomagnesemia is common in 15% of the general population, hypermagnesemia is typically only found in preeclamptic women after Mg²⁺ therapy and in patients with ESRD. Mild to moderate hypomagnesemia has been associated with hypertension, metabolic syndrome, type 2 diabetes mellitus, CKD, and cancer. Nutritional Mg²⁺ intake and enteral Mg²⁺ absorption are important for Mg²⁺ homeostasis, but the kidneys are the key regulators of Mg²⁺ homeostasis by limiting urinary excretion to less than 4% while the gastrointestinal tract loses over 50% of the Mg²⁺ intake in the feces. Here, we review the physiological relevance of Mg²⁺, the current knowledge of Mg²⁺ absorption in the kidneys and the gut, the different causes of hypomagnesemia, and a diagnostic approach on how to assess Mg²⁺ status. We highlight the latest discoveries of monogenetic conditions causing hypomagnesemia, which have enhanced our understanding of tubular Mg²⁺ absorption. We will also discuss external and iatrogenic causes of hypomagnesemia and advances in the treatment of hypomagnesemia.

Magnesium (Mg²⁺) represents the second most abundant intracellular cation in the human body, which contains 21-28 g of the element. However, regulation of Mg²⁺ homeostasis is poorly understood.^1-4 Mg²⁺ plays critical roles in enzyme activity, cellular electrophysiology, and stabilizing phospholipid and nucleoside-phosphate conjugates. Despite these significant functions, serum Mg²⁺ is often neglected in patients. Moreover, systemic Mg²⁺ depletion is surprisingly common due to declining dietary Mg²⁺, Mg²⁺-depleting effects of common medications, and diseases such as diabetes mellitus, which promote Mg²⁺ deficiency. Although mild to moderate Mg²⁺ depletion causes no overt symptoms, it likely contributes to the pathophysiology of numerous cardiovascular, endocrine, and neuropsychiatric disorders (Fig 1).^5-9 We will review the physiologic importance of Mg²⁺, the physiology of Mg²⁺ homeostasis, etiologies of Mg²⁺ deficiency, clinical assessment of Mg²⁺ status, and treatment of Mg²⁺ depletion.

Figure 1.

Human organs affected by Mg²⁺ depletion. Many different organs outlined here can be affected and dysfunctional due to hypomagnesemia.

Role of Mg²⁺ in Cell Physiology

A comprehensive review of all of the cellular activities requiring Mg²⁺ would exceed the limitations of this review, but we can briefly address the role of Mg²⁺ in 3 key clinically relevant aspects of Mg²⁺ in cell biology including cellular respiration, electrophysiology of excitable cells, and genomic stability (Fig 2).

Figure 2.

The role of Mg²⁺ in cellular physiology. Mg²⁺ plays critical roles in cells by influencing membrane potential, interacting with ion transporters, binding and stabilizing phosphate groups within nucleic acids, and contributing cellular respiration and ATP stability.

Cellular respiration depends critically upon intracellular Mg²⁺.¹⁰ Several enzymes essential for glycolysis (eg, hexokinase, pyruvate kinase, and so on) are sensitive to Mg²⁺. Mg²⁺ influences conversion of pyruvate to acetyl-coenzyme A for entry into the citric acid cycle by stimulating pyruvate dehydrogenase phosphatase. Citric acid cycle enzymes (isocitrate dehydrogenase and the alpha-ketoglutarate dehydrogenase complex) are also directly stimulated by Mg²⁺ . Oxidative phosphorylation itself depends directly upon Mg²⁺ through maintenance of the mitochondrial inner membrane potential and activity of the F₀/F₁-ATPase. Consequently, experimental dietary Mg²⁺-deficiency reduces intracellular ATP levels¹¹ and even grossly reduces body temperature.^12,13

Mg²⁺ has numerous effects on electrical activity of the cell. By electrostatically interacting with phosphate head groups in the plasma membrane, Mg²⁺ focuses the electric field gradient across the phospholipid bilayer, enhancing the electrical potential felt by voltage-gated channels.¹⁴ Mg²⁺ is an essential cofactor for activity of the Na⁺-K⁺-ATPase.¹⁵ Mg²⁺ also exerts a voltage-dependent blockade of numerous channels. Examples include cardiac K⁺ channels, the sulfonylurea receptor, the renal outer medullary K⁺ channel, voltage-dependent Ca²⁺ channels, the N-methyl-D-aspartate receptor, and the nicotinic acetylcholine receptor. The net effect of Mg²⁺ depletion on cellular electrophysiology is to promote depolarization and an increase in intracellular Ca²⁺.

Mg²⁺ also contributes to genomic stability by complexing the negatively charged sugar-phosphate backbone of DNA, stabilizing the double helix.¹⁶ Mg²⁺ is critical for high-fidelity DNA replication. It protects against mutagenesis and facilitates DNA repair. In experimental animals, Mg²⁺-deficient diets induce chromosomal aberrations and promote oncogenesis.¹⁶ In humans, lower dietary Mg²⁺ intake is associated with shorter leukocyte telomere length, suggesting that Mg²⁺ balance may influence cell senescence and aging.¹⁷

Because Mg²⁺ plays so many critical roles in cell biology, deficiency affects virtually every organ system (Fig 1).¹ We will focus on the clinically relevant importance of Mg²⁺ on the cardiovascular, endocrine, and neurologic systems.

The Role of Mg²⁺ in the Cardiovascular System

The importance of Mg²⁺ for cardiovascular health is well-established.⁵ In myocardium, depolarizing effects of Mg²⁺ depletion promote electrical irritability and arrhythmias. In vasculature, Mg²⁺ promotes vascular relaxation via blockade of L-type Ca²⁺ channels and enhanced synthesis of nitric oxide and prostacyclin. Mg²⁺ discourages formation of atheroemboli by enhancing expression of plasminogen activator inhibitor-1 and vascular cell adhesion molecule 1 and increasing cleavage of ultralarge von Willebrand factor. Reduction in interleukin 1β and interleukin-6 may contribute to Mg²⁺’s ability to slow progression of atherosclerosis. Thus, improved Mg²⁺ balance is associated with reduced hypertension, coronary artery disease, congestive heart failure, and embolic stroke.^5-9

The Role of Mg²⁺ in the Endocrine System

In pancreatic β cells, Mg²⁺ contributes to glucose-sensing and when deficient to insulin resistance.⁶ Systemically, Mg²⁺ promotes glucose uptake. As such, Mg²⁺ depletion contributes to glucose intolerance, while Mg²⁺ therapy appears to improve glucose homeostasis.^6,18

Mg²⁺ also plays a key role in bone physiology, and most of the body’s Mg²⁺ is stored in the bones.⁷ Mg²⁺ is required for parathyroid hormone (PTH) secretion and maintenance of systemic Ca²⁺ balance. Mg²⁺ depletion promotes bone turnover and reduces bone density. Placebo-controlled trials find that Mg²⁺ supplementation enhances bone density. Mg²⁺ supplementation also likely improves metabolic bone disease associated with CKD.¹⁹

The Role of Mg²⁺ in the Nervous System

Mg²⁺’s ability to enhance cell polarity and block ion channels results in numerous central nervous system effects. Migraine headache sufferers exhibit lower Mg²⁺ levels, and Mg²⁺ supplementation is possibly effective in improving migraine symptoms.^8,9 Severe Mg²⁺ depletion induces seizures. Depression is also associated with reduced Mg²⁺ levels. Patients with Alzheimer disease exhibit lower Mg²⁺ levels, which may contribute to pathogenesis of the disease by promoting neuronal excitotoxicity and inflammation.

Mg²⁺ Transport and Monogenetic Causes of Hypomagnesemia

A summary of the monogenetic diseases contributing to hypomagnesemia is provided in Table 1.

Table 1.

List of Inherited Forms of Hypomagnesemia

Disorder	Inheritance	Electrolyte Changes	Gene (Protein)	Function
Hypercalciuric hypomagnesemias
Familial hypomagnesemia with hypercalciuria and nephrocalcinosis	AR	Mg2+↓, uMg2+↑, uCa2+↑, NC	CLDN16 (Claudin-16)	Tight junction protein
Familial hypomagnesemia with hypercalciuria and nephrocalcinosis plus ocular involvement	AR	Mg2+↓, uMg2+↑, uCa2+↑, NC	CLDN19 (Claudin-19)	Tight junction protein
Classical Bartter syndrome (type 3)	AR	K+↓, Mg2+↓, HCO3−↑, uNa+↑	ClC-Kb (ClC subunit B)	Basolateral chloride channel
Autosomal dominant hypocalcemia/Bartter syndrome (type 5)	AD	Ca2+↓, Mg2+↓, uCa2+↑, uMg2+↑	CASR (CaSR)	Calcium sensing receptor
Gitelman-like hypomagnesemias
Gitelman syndrome	AR	Mg2+↓, K+↓, HCO3−↑, uCa2+↓, uMg2+↑	SLC12A3 (NCC)	Na+-Cl− cotransporter
Antenatal Bartter syndrome with sensorineural deafness (type 4)	AR	K+↓, Mg2+↓, HCO3−↑, uNa+↑	BSND (Barttin)	Subunit of ClC-Ka/b
EAST/SeSAME syndrome	AR	Mg2+↓, K+↓, HCO3−↑, uCa2+↓, uMg2+↑, uNa+↑, uK+↑	KCNJ10 (Kir4.1)	Basolateral potassium channel
Proximal and distal tubulopathy with deafness	AR	K+↓, HCO3−↓, uNa+↑	KCNJ16 (Kir5.1)	Basolateral potassium channel
Renal hypomagnesemia, refractory seizures and intellectual disability	AD	Mg2+↓, K+↓, uMg2+↑, uK+↑	ATP1A1	Na+/K+-ATPase (α subunit)
Isolated dominant hypomagnesemia	AD AD	Mg2+↓, uCa2+↓, uMg2+↑	FXYD2 (FXYD2) KCNA1 (Kv1.1)	Na+/K+-ATPase (γ subunit) apical potassium channel
HNF1B nephropathy	AD	Mg2+↓, uMg2+↑, uCa2+↓	HNF1B (HNF1beta)	Transcription factor
Hypomagnesemia after transient neonatal hyperphenylalaninemia	AR	Mg2+↓, K+↓, uMg2+↑	PCBD1 (PCBD1)	Tetrahydrobiopterin metabolism
Gitelman-like syndrome	mtDNA	Mg2+↓, uMg2+↑, uCa2+↓	MT-TF and MT-TI	Mitochondrial complex 4 stimulates NCC/OXPHOS
Autosomal dominant kidney hypomagnesemia (ADKH)	AD	Mg2+↓, K+↓, Cl−↓, uMg2+↑, uNa+↑	RRAGD	Small Rag GTPase, stimulate mTOR signaling
Other hypomagnesemias
Isolated recessive hypomagnesemia	AR	Mg2+↓, uMg2+↑	EGF (Pro-EGF)	Epidermal growth factor
Hypomagnesemia with secondary hypocalcemia	AR	Mg2+↓, Ca2+↓, uMg2+↑	TRPM6 (TRPM6)	Apical Mg2+ channel
Hypomagnesemia with impaired brain development	AD/AR	Mg2+↓, uMg2+↑	CNNM2 (CNNM2)	Cyclin M2
Hypomagnesemia with metabolic syndrome	maternal	Mg2+↓, uMg2+↑, uCa2+↓	MTTI (MTTI)	Mitochondrial tRNA for isoleucine
Hyperuricemia, pulmonary hypertension
Hyperuricemia, pulmonary hypertension and progressive renal failure (HUPRA)	AR		SARS2 (SARS2)	Seryl-tRNA synthetase

Abbreviations: Ca²⁺,calcium; Cl⁻, chloride; K⁺, potassium; HCO3’, bicarbonate; Mg²⁺, magnesium; Na⁺, sodium; NC, nephrocalcinosis; u, urine; ↓, upregulated, ↓, downregulated.

The Gastrointestinal Tract

An average of 420 mg of daily Mg²⁺ intake is recommended for men and 320 mg for women.²⁰ The gastrointestinal (GI) tract typically absorbs 30%-50% of the ingested Mg²⁺ but can increase absorption to as high as 80% (Fig 3).²¹ Dependent on the section of the GI tract Mg²⁺ absorption keeps rising with increased Mg²⁺ intake (“nonsaturable”), while in other GI tract sections, Mg²⁺ absorption will reach a limit (“saturable”) and additional Mg²⁺ intake will be lost in the feces. In general terms, paracellular transport provides often nonsaturable absorption, while transcellular absorption is frequently saturable. In the small intestine, Mg²⁺ is mostly absorbed in a paracellular and nonsaturable fashion. In the cecum and colon, Mg²⁺ undergoes saturable transcellular absorption via the Mg²⁺-selective TRPM6/TRPM7 channels (Fig 4). Overall, Mg²⁺ absorption in the GI tract is not as tightly regulated as in the kidney and is mainly dependent on Mg²⁺ intake.

Figure 3.

Mg²⁺ homeostasis in the human body. The kidneys, intestine, and bones are the main organs involved in Mg²⁺ homeostasis. Of the total body Mg²⁺, 50%-60% is stored in the skeleton, and 39% is located intracellularly, mainly in muscle (30%) and other tissues (10%-20%). Less than 1% of total body Mg²⁺ is in extracellular fluid. The intestinal Mg²⁺ absorption is ~120 mg/d, and intestinal secretion accounts for 20 mg/d, resulting in a net intestinal absorption of 100 mg/d. The kidney filters ~2400 mg/d and only excretes about 100 mg/d, while 2300 mg of Mg²⁺ are reabsorbed. Net intestinal absorption matches urinary net Mg²⁺ excretion. Bones and muscles are the most important Mg²⁺ stores. Of the intracellular Mg²⁺ about 60% is ionized, 30% of Mg²⁺ is protein bound and 10% Mg²⁺ is complexed. The concentration of free cytosolic and extracellular Mg²⁺ is very similar but because Mg²⁺ is highly bound intracellularly, the total intracellular Mg²⁺ content is much higher with 9.5 g compared to 280 mg in the extracellular fluid space.

Figure 4.

Mg²⁺ absorption in the GI tract. Intestinal Mg²⁺ absorption occurs in a paracellular mode and in a transcellular mode. Mg²⁺ absorption is low in the duodenum due to unfavorable electrochemical gradients. In further distal GI parts such as the jejunum and ileum Mg²⁺ absorption is driven by a high luminal Mg²⁺ concentration and the lumen-positive transepithelial voltage. Claudin-16 and -19, which play an important role in paracellular Mg²⁺ absorption in the TAL, are not expressed in the intestine. In the cecum and colon, the Mg²⁺ channels TRPM6 and TRPM7 are expressed on the luminal side of the enterocytes. Abbreviations: GI, gastrointestinal; TAL, thick ascending limb.

The Kidney—The Proximal Tubule

The kidneys provide critical regulation of total body Mg²⁺ homeostasis. Seventy percent to 80% of serum Mg²⁺ is filtered in the glomerulus. The renal tubule then reabsorbs in excess of 96% of this. The renal handling of Mg²⁺ is surprisingly different from other filtered cations. The proximal tubule (PT) absorbs about two-thirds of the filtered load for Na⁺, K⁺, and Ca²⁺, whereas only 10-30% of Mg²⁺ is absorbed in the PT (Fig 5). Mg²⁺ absorption in the PT occurs in a linear and unsaturable fashion in a passive, paracellular mode and is mostly unregulated. Understanding of molecular mechanisms of Mg²⁺ absorption in the PT is very limited. One mechanism includes Claudin-10a, which is abundant as a paracellular protein and is responsible for Cl⁻ absorption. The Cl⁻ absorption eventually turns the charge in the lumen in the further distal parts of the thick ascending limb (TAL) positive and so provides a driving force for paracellular Mg²⁺ absorption. In a Claudin-10a knockout mouse, Claudin-2 expression increased, permitting more paracellular Mg²⁺ absorption and resulting in hypermagnesemia.²²

Figure 5.

Mg²⁺ absorption along the nephron. In contrast to many other electrolytes, only 10-30% of filtered Mg²⁺ is absorbed in the PT, mostly in a paracellular fashion. Most of the filtered Mg²⁺ is absorbed in the TAL with 65-70%, again in a paracellular fashion driven by the lumen-positive transepithelial potential. In the DCT only 5-10% of filtered Mg²⁺ is absorbed, but here it is determined how much of the Mg²⁺ is lost in the urine. Less than 4% of filtered Mg²⁺ is excreted in the urine. Abbreviations: DCT, distal convoluted tubule; PT, proximal tubule; TAL, thick ascending limb.

The Kidney—the TAL of Henle

The preponderance of filtered Mg²⁺ (65%-70%) is absorbed in the TAL. The importance of the TAL is underscored by urinary Mg²⁺ wasting observed in patients treated with loop-diuretics. Loop-diuretics block the apical Na⁺-K⁺-2Cl⁻ cotransporter which is crucial to generate the lumen-positive transepithelial potential difference (+10 mV) required for paracellular reabsorption of Mg²⁺ in the TAL (Fig 6).^23-25 Most of the genetic conditions that disrupt the TAL concomitantly cause Mg²⁺ and Ca²⁺ wasting by reducing this lumen-positive transepithelial potential.

Figure 6.

Mg²⁺ absorption in the TAL. Apical NKCC2 facilitates cotransport of Na⁺, K⁺, and 2 Cl⁻ in an electroneutral fashion. Because K⁺ is already highly abundant intracellularly, K⁺ is immediately secreted via the apical renal outer medullary K⁺ channel (ROMK). This transport includes only a cation and therefore contributes to the lumen positive potential, which serves as the major driving force for paracellular Mg²⁺ absorption between epithelial cells. It remains unclear if Claudin-16/-19 create a paracellular Mg²⁺ pore or if they are required to form the dilution potential. The dilution potential may be created by Claudins-16 and -19 as they may determine the movement of Na⁺ and Cl⁻ back from the renal interstitium to the tubular lumen (“backleak”) to further increase the lumen positive potential. On the basolateral side, the Na⁺-K⁺-ATPase and the Cl⁻ channel ClC-Kb together with the subunit Barttin influence Mg²⁺ absorption. Mutations in α and γ subunits of the Na ⁺-K⁺-ATPase (encoded by ATP1A1 and FXYD2), the Cl⁻ channel ClC-Kb and BSND (encoding Barttin) also result in hypomagnesemia (Table 1). Classical Bartter syndrome (type III) is caused by recessive CLCNKB mutations, which encodes ClC-Kb. When the patients get older, they can develop a Gitelman-like phenotype with hypocalciuria and hypomagnesemia. A crucial subunit of ClC-Kb is Barttin, and recessive mutations in the corresponding gene BSND result in Bartter syndrome type IV and deafness. These patients can also develop hypomagnesemia but usually do not display hypercalciuria and are therefore included in the Gitelman-like hypomagnesemias. CLCNKB and BSND mutations are thought to affect intracellular Cl⁻ regulation, which alters intracellular WNK4 levels, NCC (in the DCT), and NKCC2 function and interferes with the generation of the lumen-positive potential. In the TAL CaSR is localized at the basolateral membrane and when it binds to Mg²⁺ Claudin-14 is stimulated which in turn inhibits Claudins-16/-19 thereby reducing Mg²⁺ and Ca²⁺ paracellular movement. CaSR stimulation also inhibits NKCC2 and ROMK. In contrast, stimulation of PTH receptor inhibits Claudin-14 and results in less downregulation of Claudin-16/-19, and may result in more paracellular Mg²⁺ absorption. Stimulation of the basolateral PTH receptor (PTHR) enhanced Mg²⁺ transport in rat TAL.²³ This may be mediated by a downregulation of Claudin-14 as deleting PTHR in the TAL and DCT caused a Claudin-14 increase and hypercalciuria.²⁴ Abbreviations: DCT, distal convoluted tubule; NKCC2, Na⁺-K⁺-2Cl⁻ cotransporter; PT, proximal tubule; TAL, thick ascending limb.

In the TAL, paracellular Mg²⁺ reabsorption depends upon tight junctions formed by claudin heteromers. Mutations in CLDN16 or CLDN19, causing loss of function of Claudin-16 or -19, respectively, cause autosomal recessive familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC).^26,27 Typically, individuals who are compound heterozygous or homozygous develop urinary Ca²⁺ and Mg²⁺ wasting, nephrocalcinosis, CKD in their teens and may require dialysis in their 20s to 30s. Patients with complete loss-of-function CLDN16 mutations progress more rapidly with CKD and present earlier than patients with partial-loss-of-function mutations.²⁸ When treated with furosemide, patients with FHHNC still develop increased Na ⁺ excretion but fail to increase urinary Ca²⁺ and Mg²⁺ compared to control patients.²⁹ CLDN19 mutations result in kidney manifestations indistinguishable from CLDN16 mutations but also cause ocular effects that may include myopia, nystagmus, or coloboma. Patients with FHHNC require Mg²⁺ supplementation for hypomagnesemia. Although hydrochlorothiazide has been used in an attempt to reduce nephrocalcinosis, no data yet address whether this increases renal longevity. It remains unclear whether Claudin-16 forms a Mg²⁺ pore or contributes to the lumen positive potential required for Mg²⁺ reabsorption (Fig 6).^30,31 Claudin-16 and -19 are most abundant in the TAL, but are expressed to a lesser degree in the distal convoluted tubule (DCT). Known FHHNC mutations disturb hetero-oligomerization of Claudins-16 and -19. Claudin-16 only interacts with Claudin-19, while Claudin-19 interacts with other Claudins along the TAL. Claudin-10b is also highly abundant in the TAL.³² Recessive mutations in CLDN10, encoding Claudin-10b, result in the HELIX syndrome (hypohidrosis, electrolyte imbalance, lacrimal gland dysfunction, ichthyosis, and xerostomia), characterized by metabolic alkalosis, salt wasting, hypokalemia, hypocalciuria, and hypermagnesemia.³³ Tubule-specific Claudin-10 knockout mice exhibit lower TAL Na ⁺ permeability and higher Mg²⁺ and Ca²⁺ permeabilities. Discrete regions of the TAL appear to specialize in paracellular Mg²⁺ or Na⁺ reabsorption. The medullary TAL has a high abundance of Claudin-10, mediating paracellular Na⁺ absorption. In the cortical TAL, increased Claudin-16 and -19 provides Ca²⁺ and Mg²⁺ absorption.³² This mosaic expression pattern has been confirmed in single-cell RNA-sequencing studies showing that, although all TAL cells express Claudin-19, expression of Claudin-16 and -10b are mutually exclusive.³⁴

Claudin-14, encoded by CLDN14, may also modulate paracellular Mg²⁺ absorption. Highly expressed in TAL, dietary Mg²⁺ intake increases its expression.³⁵ FEMg²⁺ is lower in Claudin-14 knockout mice, whereas overexpression increases FEMg²⁺.^36,37 Claudin-14 may suppress paracellular Mg²⁺ absorption by downregulating Claudin-16 and 19. In humans, a polymorphism in the CLDN14 3′ untranslated sequence is associated with lower urinary Mg²⁺/Ca²⁺.³⁵

The calcium sensing receptor (CaSR), at the basolateral membrane of TAL cells, also influences Mg²⁺ transport in this segment. Gain-of-function mutations in CaSR mimic hypercalcemia, causing autosomal dominant hypocalcemia. About 50% of patients exhibit hypomagnesemia. Patients present with hypocalcemia, hypercalciuria, nephrolithiasis, carpopedal spasms, seizures, and inappropriately low to normal PTH. CaSR stimulation reduces Na⁺-K⁺-2Cl⁻ cotransporter and renal outer medullary K⁺ activity, attenuating the lumen-positive electrical potential required for paracellular Mg²⁺ absorption. CaSR also upregulates Claudin-14 via microRNAs mIR-9 and mIR-374 and downregulates Claudin-16 and -19.³⁸ Severe CASR gain-of-function mutations can also present with Bartter syndrome type V, also with hypomagnesemia (Fig 6).

CaSR stimulation reduces TAL Mg²⁺ reabsorption, whereas stimulation of the basolateral PTH receptor enhances Mg²⁺ transport in the isolated, perfused TAL.²³ This effect was suggested to occur through increased lumen potential.

The small guanosine triphosphatase RagD, encoded by RRAGD, was recently identified as a modifier of Mg²⁺ absorption. RagD stimulates signaling through the target of rapamycin complex 1 (mTOR1). Patients with heterozygous mutations in RRAGD develop autosomal dominant kidney hypomagnesemia.³⁹ As both the TAL and DCT express RagD, additional features include hypercalciuria, nephrocalcinosis, hypokalemia, polyuria, failure to thrive, and a tendency toward metabolic alkalosis. Some pregnancies of fetuses with RRAGD mutations were complicated by polyhydramnios, similar to Bartter syndrome. Some but not all patients also developed dilated cardiomyopathy and required a cardiac transplant.

The Kidney—The DCT

Fine-tuning of tubular Mg²⁺ occurs in the DCT, which reabsorbs about 5%-10% of filtered Mg²⁺. There is no indication of Mg²⁺ absorption more distally. Transcriptomic data suggest magnesiotropic gene expression (and subsequent Mg²⁺ absorption) in both the early DCT (DCT1) and in the late, ENaC-expressing, DCT (DCT2).³⁴ In contrast to the PT and TAL, Mg²⁺ absorption in the DCT occurs in an active, transcellular fashion (Fig 7). Most genetic conditions affecting Mg²⁺ absorption in the DCT involve different proteins affecting tubular Na⁺, K⁺, or Cl⁻ transport in the DCT and contribute so to the negative membrane potential. Many of the conditions affecting the DCT present with hypocalciuria, volume contraction, hypotension, and due to stimulation of the renin-angiotensin system with hypokalemia and metabolic alkalosis.

Figure 7.

Mg²⁺ absorption in the DCT. In the DCT, the negative membrane potential is crucial for apical Mg²⁺ absorption via TRPM6/7. Intracellular Mg²⁺ inhibits the TRPM6/7 channels. Urinary uromodulin interacts with TRPM6 and enhances TRPM6 cell surface abundance by impairing TRPM6 endocytosis. The Kv1.1 channel forms tetramers, and coexpression of WT and mutant Kv1.1 showed a dominant-negative effect of the mutant Kv1.1 channels, likely diminishing the negative membrane potential. The thiazide-sensitive NCC cotransporter is crucial for Na ⁺ absorption in the DCT but recessive mutations result in Gitelman syndrome and urinary Mg²⁺ wasting. EGF is secreted in an autocrine and paracrine fashion and binds to EGFR.⁴⁰ WT EGF binds to EGFR, a tyrosine kinase is activated which stimulates TRPM6. ARL15 enhances TRPM6 activity and downregulates CNNM2. Two subunits of the basolateral Na⁺-K⁺-ATPase also contribute to hypermagnesuria. ATPA1A mutations alter the α subunit whereas FXYD2 mutations impair the γ subunit. No intracellular Mg²⁺ binding proteins are known. Two basolateral candidates for Mg²⁺ extrusion include the Na⁺-Mg²⁺ exchanger solute carrier family 41 member A1 (SLC41A1) and A3 (SLC41A3), which are both expressed in the DCT. Inactivating recessive mutations in SLC41A1 cause a nephronophthisis-like phenotype but no serum or urine Mg²⁺ abnormalities. A knockout mouse for Slc41a3 showed hypomagnesemia but Slc41a3 may probably work in the mitochondria and not in the basolateral membrane.⁴¹ The cyclin and CBS domain divalent metal cation transport mediator-2 (CNNM2), a transmembrane protein, is also present at the basolateral membrane of the human TAL and DCT. CNNM2 mutations result in hypomagnesemia, impaired brain development, and renal Mg²⁺ wasting but some carriers remained asymptomatic. CNNM2 may be a Mg²⁺ sensor. Basolateral Kir4.1 and Kir5.1 localization is crucial for K⁺ extrusion. Kir4.1 was detected in the DCT, the brain, and the inner ear, whereas Kir5.1 is mostly found in the PT and DCT. Kcnj10^−/− mice displayed characteristics similar to human EAST/SeSame patients and displayed significant Ncc reduction, phosphorylation, urinary Mg²⁺ losses, and DCT atrophy. Kir4.1/5.1 channels form heteromeric complexes and provide K⁺ recycling for K⁺, which enters the cells for extruding Na⁺ ions. The intracellular and extracellular distribution of K⁺ is important for the creation of the negative DCT membrane potential. The basolateral Na⁺-K⁺-ATPase activity depends on the K⁺ recycling by Kir4.1/5.1, therefore impaired function of Kir4.1/5.1 may result in lower NCC activity. In the context of a lower extracellular K⁺ concentration there is a higher K⁺ efflux via Kir4.1/5.1. The K⁺ efflux is a driving force for basolateral Cl⁻ efflux via ClC-Kb, which reduces intracellular Cl⁻ levels. Cl⁻ binds directly to WNK4 and inhibits WNK4 activity. Thus, a lower intracellular Cl⁻ concentration reduces the inhibition of WNKs and subsequently enhances NCC phosphorylation by SPAK. This model also explains how hypomagnesemia occurs in classical (due to CLCNKB mutations) and antenatal (due to mutations in the β subunit Barttin, encoded by BSND, required for ClC-Kb function) Bartter syndrome. HNF1β binds to promoter binding sites of FXYD2 and HNF1β mutations impair FXYD2 transcription. HNF1β is stabilized by PCBD1 and recessive PCBD1 mutations result in proteolytic instability of the PCBD1-HNF1β complex, impaired HNF1β-mediated stimulation of FXYD2, and renal Mg²⁺ losses. The PCBD1-HNF1β complex stimulates transcription of FXYD2, and the genes encoding Kir4.1/5.1. Abbreviations: DCT, distal convoluted tubule; SPAK, SPS1-related proline/alanine-rich kinase; TAL, thick ascending limb.

At the apical membrane of the DCT, TRPM6, in conjunction with TRPM7, mediates Mg²⁺ transport.⁴² Recessive TRPM6 mutations in humans result in severe hypomagnesemia with secondary hypocalcemia.^43,44 Hypomagnesemia with secondary hypocalcemia is diagnosed in the first few months of life with profound hypomagnesemia resulting in seizures and delayed development.⁴⁵ Mice with homozygous Trpm6 deletion are not viable.⁴⁶ Surprisingly, kidney-specific Trpm6 and Trpm7 knockout mice are not characterized by Mg²⁺ wasting and are normomagnesemic.^47,48 These mice may compensate by enhancing Mg²⁺ absorption in the TAL, which may not be possible in humans. These data may also reflect greater importance of TRPM6 expression in the intestine compared to DCT. Patients with hypomagnesemia with secondary hypocalcemia also have hypocalcemia with inappropriately low PTH levels, illustrating the importance of Mg²⁺ in PTH secretion.

Several modulators of TRPM6 expression have been identified, including epidermal growth factor (EGF), uromodulin, and the ADP-ribosylation factor-like protein 15 (ARL15). EGF exerts paracrine and autocrine activation of the basolateral EGF receptor⁴⁰ (Fig 7). Mutations resulting in isolated, recessive hypomagnesemia (IRH) reduce EGF secretion and cause renal Mg²⁺ wasting, seizures, and developmental delay but no other electrolyte abnormalities. EGF-blocking antibodies cetuximab and panitumumab used in treatment of EGF-overexpressing cancers also cause hypomagnesemia.⁴⁰ Uromodulin, the most abundant urinary protein, increases in response to a low-Mg²⁺ diet.⁴⁹ Uromodulin in the tubular lumen interferes with endocytosis of TRPM6 channels, enhancing abundance at the cell surface and facilitating transcellular Mg²⁺ reabsorption. Additionally, uromodulin promotes cell surface expression of Na⁺-K⁺-2Cl⁻ cotransporter, and loss of uromodulin may reduce paracellular Mg²⁺ reabsorption in the TAL. ARL15 encodes a GTP-binding protein expressed in the TAL and DCT. A human intronic ARL15 variant correlated with lower 24-hour urinary Mg²⁺ excretion.⁵⁰ Coexpression of ARL15 and TRPM6 enhances TRPM6 activity.⁵⁰

Other channels and cotransporters in the DCT influence Mg²⁺ reabsorption indirectly (Fig 7). The voltage gated potassium channel subtype 1.1 (Kv1.1) contributes to a DCT apical membrane potential of −70 mV that drives Mg²⁺ entry through TRPM6/M7 channels.⁵¹ Heterozygous KCNA1 mutations (encoding Kv1.1) result in isolated dominant hypomagnesemia, characterized by profound hypomagnesemia causing muscle cramps, tetany, developmental delay, and seizures, as well as hypocalciuria without extracellular fluid volume depletion.⁵¹ While all KCNA1 mutations also cause ataxia and myokymia (a localized muscle trembling), only the Asn to Asp mutation at position 255 results in hypomagnesemia. Mutation of FXYD2, encoding the γ subunit of the Na⁺-K⁺-ATPase, also causes isolated dominant hypomagnesemia. Gly to Arg substitution at amino acid 41 results in impaired trafficking and perinuclear accumulation.⁵² Similarly, mutations in the α-1 subunit (ATPA1A) of the Na⁺-K⁺ ATPase also cause hypermagnesuria.⁵³

NCC activity is an important determinant of DCT Mg²⁺ absorption. NCC blockade by thiazides or deletion in mice cause urinary Mg²⁺ wasting. Human recessive mutations in SLC12A3, encoding NCC, cause Gitelman syndrome, with a frequency of 1:40,000. Characteristics of Gitelman syndrome are hypokalemic alkalosis, hypocalciuria, and hypomagnesemia. Symptoms include muscle weakness, fatigue, salt craving, thirst, carpopedal spasms, and nocturia, but the clinical spectrum is quite variable ranging from asymptomatic to severely impacting quality of life. In up to 40% of patients, the second recessive mutation is not identified because it is likely localized deep in an intron or large genomic rearrangements. Urinary Mg²⁺ wasting is thought to occur due to a reduced Trpm6 expression in the absence of NCC. Alternate hypotheses include DCT atrophy due to NCC deficiency, K⁺ depletion, or impaired Na⁺-K⁺ ATPase activity due to impaired apical Na⁺ entry, depolarizing the cell and reducing the driving force for apical Mg²⁺ reabsorption. Patients with Gitelman syndrome require lifelong Mg²⁺ and possibly K⁺ therapy and K⁺-sparing diuretics such as amiloride, spironolactone, or eplerenone.

Basolateral inwardly rectifying K⁺ channels Kir4.1/5.1, encoded by KCNJ10 and KCNJ16, also contribute to Mg²⁺ reabsorption by recycling K⁺ which enters the cells for extruding Na⁺ via the Na⁺-K⁺-ATPase (Fig 7). Recessive mutations in KCNJ10, expressed in DCT and the connecting tubule, result in early infantile hypomagnesemia, hypokalemic metabolic alkalosis, hypocalciuria, seizures, speech and motor delay, ataxia, tremor, dysdiadochokinesia, and hearing impairment.^54,55 The associated syndrome has been described as EAST (epilepsy, ataxia, sensorineural deafness, and salt losing tubulopathy) or SeSame syndrome.⁵⁴ A similar phenotype was found for patients with recessive KCNJ16 mutations (broadly expressed throughout the tubule) except that these patients had no seizures and no ataxia.⁵⁵

There are increasing links that tie apical NCC, basolateral Kir4.1/5.1 and the basolateral Cl⁻ channel ClC-Kb (mutated in classical Bartter syndrome), together through the with-no-lysine [K] (WNK)-SPS1-related proline/alanine-rich kinase regulatory system (Fig 7). Impaired Cl⁻ efflux due to ClC-Kb or Barttin (BSND) mutations result in higher WNK inhibition and lower NCC activity.

The transcription factor hepatocyte nuclear factor 1β (HNF1β), a member of the homeodomain-containing superfamily, also regulates Kir4.1/5.1 and FXYD2. Dominant mutations in HNF1β are the most common genetic cause for congenital abnormalities of the kidney and urogenital tract and result in autosomal-dominant tubulo-interstitial kidney disease. About 50% of patients with HNF1β mutations develop hypomagnesemia and hypocalciuria.⁵⁶ HNF1β is stabilized by the dimerization cofactor PCBD1, which if mutated also causes hypomagnesemia after transient neonatal hyperphenylalaninemia.⁵⁷ HNF1β mutations cause a wide spectrum of symptoms including hyperechogenic kidneys, multicystic and glomerulocystic kidney disease, renal hypoplasia, renal agenesis, hyperuricemic nephropathy, renal cysts and diabetes syndrome, and maturity-onset diabetes of the young type 5. A large number of HNF1β mutations occur de novo and include larger deletions, which can be missed by Sanger sequencing.

Mitochondrial Hypomagnesemias

Several reports demonstrate the importance of mitochondrial function in Mg²⁺ handling. These describe mtDNA mutations influencing tRNA synthesis and resulting in Gitelman-like disorders, characterized by hypomagnesemia and hypocalciuria.^58-60 The importance of mitochondria in DCT activity is demonstrated by the observation that pharmacological inhibition of the electron transport chain attenuates NCC phosphorylation, reducing Na⁺ reabsorption; however, mechanisms by which mitochondrial dysfunction causes hypomagnesemia remain unclear.

ADDITIONAL CAUSES OF Mg²⁺ DEPLETION

A wide range of environmental factors and medications contribute to Mg²⁺ depletion (Table 2). Over 60% of Americans fail to consume the recommended daily Mg²⁺.⁴ Changes in farming practices and in food processing have dramatically reduced the Mg²⁺ content of food, and it is becoming harder to consume a diet with adequate Mg²⁺.^61,62 Dietary fat and alcohol also lead to the depletion of Mg²⁺.^63-65 Dietary acid stress enhances urinary Mg²⁺ loss through downregulation of TRPM6 in the kidney.⁶⁶

Table 2.

Medications and Medical/Environmental Etiologies Causing Hypomagnesemia

Environmental/Medications Contributing to Hypomagnesemia	Mechanism
Environmental conditions
Dietary deficiency	Inadequate intake
High-fat diet	Decreased absorption
Medical conditions
Pancreatitis	Malabsorption
Inflammatory bowel disease	Malabsorption
Celiac disease	Malabsorption
Chronic diarrhea	Malabsorption
Short gut syndrome	Malabsorption
Small bowel bypass surgery	Malabsorption
Proton pump inhibitors (omeprazole, pantoprazole)	pH Effect, decreased intestinal Mg2+ reabsorption via TRPM6 (7) Tubulointerstitial nephritis
Enhanced urinary excretion
Alcoholism	Malnourishment, dietary deficiency
Antibody against Claudin-16	Formation of Claudin-16 autoantibodies
Antimicrobials (eg, aminoglycosides, amphotericin B, pentamidine)	PT damage, Fanconi syndrome
Calcineurin inhibitors (eg, cyclosporine A, tacrolimus)	Claudin-16 downregulation TRPM6 downregulation
Loop diuretics	↓ lumen positive potential difference in TAL
Thiazide diuretics	Impaired DCT function
Epidermal growth factor receptor inhibitor (eg, cetuximab)	Blockade of EGF receptor and lack of TRPM6 stimulation
Platinum derivatives (eg, cisplatin, carboplatin)	Necrotic nephropathy, PT and DCT injury

Abbreviations: DCT, distal convoluted tubule; EGF, epidermal growth factor; PT, proximal tubule; TAL, thick ascending limb.

Gastrointestinal illness can provoke hypomagnesemia by impairing absorption of Mg²⁺. Examples of these include short gut syndrome, inflammatory bowel disease, celiac disease, and pancreatitis.

Mg²⁺ depletion is underappreciated as a key feature of diabetes mellitus. In a cohort of 1983 patients with diabetes mellitus, we observed a mean serum Mg²⁺ of 1.90 ± 0.33 Mg/dL (SD), as compared to 2.01 ± 0.25 Mg/dL in 12,829 nondiabetic controls (P < 0.0001) (unpublished data as seen in UPMC Health system patients aged 18 to 70 years, excluding transplant recipients). Similar findings have been previously published.^67-69 Mg²⁺ depletion also impairs glucose tolerance, but diabetes also promotes Mg²⁺ depletion, thus Mg²⁺ depletion and diabetes have been suggested to engage in a vicious cycle.⁶

Congestive heart failure is associated with Mg²⁺ depletion. This may occur secondary to hyperaldosteronism. However, diuretics—discussed below—may also contribute. Mg²⁺ depletion may contribute to the pathophysiology of heart failure by impairing cellular energetics and the ability of cardiomyocytes to reduce cytosolic Ca²⁺.⁷⁰

Numerous medications deplete Mg²⁺. Loop and thiazide diuretics enhance urinary Mg²⁺ excretion. Proton pump inhibitors impair intestinal Mg²⁺ absorption.⁷¹ Calcineurin inhibitors such as tacrolimus downregulate Claudin-16 and TRPM6, inducing renal Mg²⁺ wasting.^72,73 As discussed above, EGF receptor antagonism reduces TRPM6 expression, causing urinary Mg²⁺ loss.⁴⁰ Antimicrobials such as aminoglycosides and amphotericin B also cause urinary Mg²⁺ wasting.^74,75 Finally, platinum containing chemotherapy causes long-lasting and profound hypomagnesemia due to necrotic nephropathy with injury of the PT and DCT.⁷⁶ Interestingly, autoantibody formation against Claudin-16 also can result in hypomagnesemia and renal Mg²⁺ wasting.⁷⁷

ASSESSMENT OF SYSTEMIC Mg²⁺ STATUS AND RENAL Mg²⁺ HANDLING

Numerous methods have been assessed to evaluate bodily Mg²⁺ status, including measurement in numerous tissues and assessment of urinary Mg²⁺ retention. Serum or plasma Mg²⁺ are used most frequently in clinical settings. These are typically measured using photometric dyebinding assays; however, enzyme-based colorimetric assays or atomic absorption spectroscopy may also be employed, as reviewed recently.⁷⁸

Normal serum Mg²⁺ in the United States was described as part of the National Health and Nutrition Examination Survey I study.⁷⁹ Amongst adults, the 95% reference range for Mg²⁺ was 0.75 to 0.96 mmol/L (1.82 to 2.32 Mg/dL). Sex and race differences were minimal. Adults exhibited little age-dependent difference in Mg²⁺, but levels in infants of approximately 1 year of age exhibited 0.035 to 0.85 mmol/L higher Mg²⁺ than 18- to 24-year-old individuals. Data regarding diurnal variation are not conflicting.

Only ~0.3% of the body’s Mg²⁺ resides in serum, and serum Mg²⁺ poorly reflects systemic stores. In patients with high likelihood of Mg²⁺ depletion based on clinical history, a serum cutoff of 0.7, 0.75, or 0.8 mmol/L (1.7, 1.82, or 1.94 Mg/dL) was associated with clinical evidence of Mg²⁺ deficiency in 90%, 50%, and 10% of patients, respectively.⁸⁰ These findings suggest that the reference range of 0.75 to 0.96 mmol/L (1.82 to 2.32 Mg/dL) defined as part of National Health and Nutrition Examination Survey 1 fails to identify Mg²⁺ depletion in many individuals. Citing the public health importance of Mg²⁺ depletion and the insensitivity of serum Mg²⁺ in detecting it, 2 sets of authors have advocated a reference range with a lower limit of 0.85 mmol/L (2.07 Mg/dL).^81,82

Serum Mg²⁺ correlates most closely with bone Mg²⁺ —likely reflecting rapid exchange between these compartments.⁸³ By contrast, serum Mg²⁺ correlates poorly with intracellular Mg²⁺.^84,85 Intracellular erythrocyte Mg²⁺ measurement is available through many clinical laboratories. In patients with diabetes, erythrocyte Mg²⁺ levels are lower, increase in response to supplementation, and correlate with urinary retention of an infused Mg²⁺ load (discussed below). However, erythrocyte Mg²⁺ is influenced by cell age, storage conditions after phlebotomy, and measurement site.⁸⁴ Because 30% of the body’s Mg²⁺ resides in muscle, muscle Mg²⁺ concentrations may be a better indicator of intracellular Mg²⁺ status, though not feasible for routine clinical monitoring.

Urinary Mg²⁺ has been advocated to assess bodily Mg²⁺ status. At steady state, urinary Mg²⁺ excretion reflects intestinal Mg²⁺ absorption, not systemic stores. In principle, systemic Mg²⁺ depletion may enhance renal tubular Mg²⁺ reabsorption, which can be assessed by measuring urinary retention of an acute Mg²⁺ load. This can be accomplished by pairing an intravenous infusion of Mg²⁺ with a 24-hour urine collection. Retention of more than 20% to 28% indicates Mg²⁺ depletion, as observed in subjects with alcoholism or diabetes.^85-87 Unfortunately, clinical use of this method is generally impractical, and interpretation is difficult in patients with altered kidney function.

When urinary Mg²⁺ wasting is suspected, this can be confirmed by examination of the fractional excretion of Mg²⁺ (FEMg):

$$\mathrm{FEMg}={100}^{\ast }{[\mathrm{Mg}]}_{\text{urine}}\times {[\text{Creatinine}]}_{\text{serum}}∕(0.8\times [\mathrm{Mg}]{{}_{\text{serum}}}^{\ast }{[\text{Creatinine}]}_{\text{urine}})$$

Serum [Mg²⁺] is multiplied by 0.8 to reflect incomplete filtration of Mg²⁺ in the glomerulus. In patients with normomagnesemia, the FEMg should be less than 4%. In Mg²⁺ depletion, healthy kidneys should reduce the FEMg to less than 2%. Higher levels indicate renal tubular Mg²⁺ wasting. Mg²⁺ consumption in supplements or meals could influence the FEMg. When in doubt, measurement of urine [Mg²⁺] and creatinine from a 24-hour collection may be reasonable. FEMg, urine Mg²⁺/Ca²⁺ ratio, and 24-hour excretion of Mg²⁺ have been used successfully in a research context to better assess total body Mg²⁺ status.⁸⁸ The high prevalence of systemic Mg²⁺ depletion combined with limited ability to formally demonstrate systemic Mg²⁺ deficiency suggests that clinicians should have a low threshold to empirically address Mg²⁺ depletion.

TREATMENT OF Mg²⁺ DEPLETION

Improved dietary Mg²⁺ intake represents the simplest step in improving Mg²⁺ stores. Counseling should include education regarding high Mg²⁺ foods, such as brans (eg, wheat or rice bran), seeds (eg, pepitas and sunflower seeds), and nuts.⁸⁹ A meta-analysis of 41 studies estimated that 1 day’s intake of organically farmed produce would provide 16.6% more Mg²⁺ compared to nonorganically farmed produce.⁹⁰ Whole grain wheat flour contains 3.5 to 6.7 fold more Mg²⁺ than “white” wheat flour.⁹¹ Clearly, these differences can impact Mg²⁺ balance.

Oral supplements vary considerably in terms of absorption and tendency to cause loose stools (Table 3). In laboratory animals, out of several Mg²⁺ salts examined, Mg²⁺ malate had the biggest impact on plasma Mg²⁺ concentration.⁹² In humans, rank-order absorption of Mg²⁺ salts were shown to be aspartate >lactate>>citrate>glycinate>oxide>chloride>gluconate.⁹³ Mg²⁺ acetate was absorbed significantly better than a slow-release Mg²⁺ chloride formulation.⁹⁴ Mg²⁺ aspartate, lactate and slow-release chloride all increased urinary Mg²⁺ concentrations compared to controls; only Mg²⁺ oxide did not.⁹⁵ The discrepancy in chloride findings may reflect improved absorption with slow-release formulations. Thus, organic Mg²⁺ salts are generally best absorbed, followed perhaps by Mg²⁺ chloride, then Mg²⁺ oxide. Tendency to cause loose stools is likely inversely proportional to absorbability of the salts.

Table 3.

Oral Magnesium Supplement Preparations

Magnesium Salt	Relative Cost	Likely Absorption In Humans
Oxide	¢	+
Citrate	$	++
Malate	$	+++
Aspartate	$	+++
Chloride	$$	+
Glycinate	$$	++
Gluconate	$$$	++
Lactate	$$$	+++
Threonate	$$$$

Relative cost is based on mean prices of 3 or more products from an online retailer. Only tablets or capsules were compared (no powders or liquids). Sustained release formulations were excluded. Relative absorption is based on human data,^93-95 except for magnesium malate.⁹²

In patients with severe Mg²⁺ depletion or inadequate intestinal Mg²⁺ absorption, supplements may not sufficiently raise blood Mg²⁺ levels. Fortunately, adjunctive therapies can enhance renal tubular reabsorption of Mg²⁺.

One strategy to enhance renal tubular reabsorption of Mg²⁺ is through pharmacologic inhibition of the epithelial sodium channel (ENaC) in the distal nephron. Na⁺ permeability through ENaC in the connecting tubule and collecting duct reduces the electrical potential of the lumen. Blockers of ENaC or mineralocorticoid antagonists, which reduce ENaC expression, attenuate this effect.^96,97 A more positive lumen potential would, in principle, enhance Mg²⁺ reabsorption in tubular segments expressing ENaC and Mg²⁺ transporters. In patients with healthy kidneys, the ENaC blockers triamterene and amiloride increase serum Mg²⁺ by 0.021 to 0.102 mmol/L (0.05 to 0.248 mg/dL).^98,99 The relatively short elimination half-life of amiloride (6 to 9 hours) suggests that dosing more frequently than daily could be helpful.¹⁰⁰

ENaC antagonism may not be effective in all patients. In patients with hypomagnesemia due to Gitelman syndrome, although amiloride reduced urinary Mg²⁺ excretion, the Mg²⁺-retentive effect was not strong enough to significantly increase serum Mg²⁺.¹⁰¹ Inability of ENaC blockade to increase serum Mg²⁺ in Gitelman syndrome is consistent with a mechanism that requires enhanced activity of TRPM6 in the second portion of the DCT, where ENaC and TRPM6 expression overlap.¹⁰² These findings suggest the ability of ENaC blockers to increase serum Mg²⁺ may depend upon the pathophysiologic mechanisms causing Mg²⁺ depletion.

Although mineralocorticoid receptor antagonists reduce ENaC expression in the aldosterone sensitive distal nephron, their impact on serum Mg²⁺ levels is weaker than direct ENaC blockers.^103-105 The reduced ability of mineralocorticoid receptor antagonists to increase Mg²⁺ compared to ENaC blockers may be explained by the observation that ENaC expression in proximity to TRPM6 occurs relatively independently of aldosterone.¹⁰⁶

Inhibitors of the PT’s sodium glucose transporter type 2 (SGLT2) provide a new tool to enhance tubular reabsorption of Mg²⁺. A meta-analysis of circulating Mg²⁺ levels found that the use of SGLT2 inhibitors was associated with significantly increased circulating Mg²⁺ levels, regardless of the specific agent used.¹⁰⁷ In patients with severe urinary Mg²⁺ wasting and diabetes mellitus, SGLT2 inhibition reduced fractional excretion of Mg²⁺ and attenuated hypomagnesemia.¹⁰⁸ SGLT2 inhibitors also appear to increase calcineurin inhibitor-associated hypomagnesemia by roughly 0.05 mmol/L (0.12 Mg/dL).¹⁰⁹ The mechanism behind these observations may include increased lumen potential in the PT, improving the driving force for paracellular Mg²⁺ reabsorption.¹¹⁰ Other mechanisms, including increased Na⁺ delivery to more distal nephron segments, promoting increased Mg²⁺ reabsorption in those segments, may also contribute.¹¹¹ The preponderance of human data thus far examines Mg²⁺ handling in diabetic individuals. Efficacy in nondiabetic individuals remains unclear.

Improving gastrointestinal absorption of Mg²⁺ can also improve hypomagnesemia. Nondigestible oligosaccharides, such as inulin and fructo-oligosaccharides, enhance intestinal absorption of Mg²⁺.¹¹² Bacterial fermentation of these fructans produces short-chain fatty acids and acidifies luminal contents, either of which may promote Mg²⁺ absorption. In small human trials, dietary supplementation of fermentable oligosaccharides tended to increase Mg²⁺ balance, though not always with statistical significance. Fermentable oligosaccharides were not successful in increasing Mg²⁺ balance in patients with ileostomy, but did ameliorate proton pump inhibitor-induced hypomagnesemia.¹¹³ Side effects include flatulence, borborygmi, or loose stools, but these effects reportedly resolve in 2 to 3 days. If tolerated, dietary inulin may improve Mg²⁺ balance in some patients.

Agonists of the glucagon-like peptide (GLP-2) receptor have potential to improve hypomagnesemia. GLP-2 receptor agonism increases intestinal mucosal surface area, blood flow, and reduces gastrointestinal motility. Teduglutide, a synthetic GLP-2 receptor agonist, is used to enhance intestinal absorption in subjects with short bowel syndrome. A case report of 2 patients with refractory hypomagnesemia in association with short bowel syndrome secondary to Crohn’s disease described one patient as no longer needing intravenous Mg²⁺ infusions and another as no longer needing nasogastric Mg²⁺ supplementation following initiation of teduglutide.¹¹⁴ However, a randomized, placebo-controlled trial saw no mean increase in serum Mg²⁺ in short bowel syndrome subjects without clear hypomagnesemia who received teduglutide for 24 weeks.¹¹⁵ Thus, it remains unclear whether GLP-2 receptor modulation could be beneficial in patients with hypomagnesemia with, or without intestinal malabsorption.

When Mg²⁺ supplements and adjunctive therapies fail to normalize serum Mg²⁺, clinicians may be forced to consider parenteral supplementation. The salutary effects of Mg²⁺ rich mineral baths have been extolled since antiquity. Although it may be tempting to ascribe some of these benefits to Mg²⁺ absorption, scant data support the idea that Mg²⁺ is absorbed transdermally. A pilot study found no significant overall effect on serum Mg²⁺ or urinary Mg²⁺ excretion.¹¹⁶ Other controlled trials are lacking.

Parenteral Mg²⁺ infusion represents a last resort for patients with refractory hypomagnesemia. The magnitude of the effect of Mg²⁺ infusion on serum Mg²⁺ may depend upon kidney function and degree of hypomagnesemia. However, the effects of intravenous infusion in patients with robust glomerular filtration are transient, perhaps because Mg²⁺ infusion activates the CaSR in the TAL, enhancing urinary Mg²⁺ excretion.

Slower delivery may prove more effective in some patients. This can be achieved through a slow, subcutaneous depot infusion of Mg²⁺ sulfate. A review by Makowsky et al¹¹⁷ describes success with this approach in patients predominantly with refractory hypomagnesemia associated with short bowel syndrome. We have successfully managed urinary Mg²⁺ wasting with nightly subcutaneous infusion of Mg²⁺ sulfate using a small bed-side pump (manuscript in preparation). Although Mg²⁺ sulfate is only approved for use in the United States via intravenous or intramuscular injection, subcutaneous injection appears to be effective, with greater ease and fewer adverse complications compared to intravenous infusion.

A combined approach using maximally absorbed oral Mg²⁺ salts, enhancement of intestinal Mg²⁺ absorption, adjunctive therapy to enhance renal tubular Mg²⁺ reabsorption, and judicious use of parenteral infusion will maximize the likelihood that patients experience symptomatic and laboratory improvement of hypomagnesemia and may even optimize Mg²⁺ in patients with challenging hypomagnesemia.

CONCLUSION

Mg²⁺ is an important but often overlooked electrolyte, which is frequently not even tested for. Identification of new genes, causing rare forms of inherited hypomagnesemia has improved our understanding of tubular Mg²⁺ handling. In the clinical setting it is mostly side effects of medications contributing to hypomagnesemia. Therapy of hypomagnesemia remains challenging despite different forms of Mg²⁺ supplements.

CLINICAL SUMMARY.

• Mg²⁺ is a frequently overlooked electrolyte, even though mild to moderate hypomagnesemia affects 10%-15% of the general population.

• Nutritional intake and gastrointestinal Mg²⁺ absorption are crucial, but the kidneys are the key regulators of total body Mg²⁺ homeostasis.

• Discoveries of new genes causing hypomagnesemia have improved our understanding of tubular Mg²⁺ absorption.

• Mg²⁺ therapy remains a challenge due to the few but inefficient formulations of Mg²⁺ that are covered by insurances.