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.

Keywords: Distal convoluted tubule; Magnesium; Physiology; Therapies for hypomagnesemia; Thick ascending limb of Henle; Tubule.

Figure 1.

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

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.

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.

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.

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. 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. Abbreviations: DCT, distal convoluted tubule; NKCC2, Na⁺-K⁺-2Cl⁻ cotransporter; PT, proximal tubule; TAL, thick ascending limb.

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. 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. 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.