Disorders of Magnesium: Physiology

Fig. 23.1

Mg²⁺ homeostasis in an adult subject. (Filtered load of Mg²⁺ equals plasma free Mg²⁺ concentration of 1.1 mg/dL times GFR of 180 L/day; i.e., 180 L × 11 mg/L = 1,980 mg/day. Note that the intake of 300 mg/day is excreted in the feces (200 mg) and urine (100 mg) to maintain Mg²⁺ homeostasis.) (Modified from Nordin B.E.C., (ed.). Calcium, Phosphate, and Magnesium Metabolism. Churchill Livingston, Edinburgh, 1976, with permission.)

Mg²⁺ homeostasis is also dependent on the exchange between the extracellular pool and bone. The Mg²⁺ available in the surface pool of the bone is involved in the homeostatic regulation of extracellular Mg²⁺.

The kidney also maintains Mg²⁺ homeostasis because it regulates the rate of excretion depending on the Mg²⁺ concentration. Normally, the excretory fraction of Mg²⁺ is 5 %. In states of Mg²⁺ deficiency, the excretion can be as low as 0.5 %. In states of Mg²⁺ excess or in chronic kidney disease, excretion can be as high as 50 %.

Renal Handling of Mg²⁺

Free and nonprotein-bound Mg²⁺ is filtered at the glomerulus. Approximately 2,000 mg of Mg²⁺ are filtered and only 100 mg are excreted in the urine, which implies that 95 % of the filtered Mg²⁺ is reabsorbed. The proximal tubule reabsorbs about 20 % of the filtered Mg²⁺. This amount is relatively low when compared to the reabsorption of Na⁺, K⁺, Ca²⁺ or phosphate at the proximal tubule. The most important segment for Mg²⁺ reabsorption is the cortical thick ascending limb of Henle’s loop. In this segment, about 40–70 % of Mg²⁺ is reabsorbed. The distal convoluted tubule reabsorbs 5–10 % of the filtered Mg²⁺, and very little reabsorption occurs in the collecting duct. Under steady state conditions, the urinary excretion of Mg²⁺ is about 5 % of the filtered load.

Proximal Tubule

The transport of Mg²⁺ in the proximal tubule is passive and unidirectional down an electrochemical gradient. It is dependent on the concentration of Mg²⁺ in the luminal fluid. Mg²⁺ reabsorption occurs in parallel with Na⁺ reabsorption and thus is influenced by changes in extracellular fluid volume .

Thick Ascending Limb of Henle’s Loop (TALH)

The transport of Mg²⁺ in the cortical TALH is both passive and active. Passive transport is dependent on the lumen-positive voltage difference secondary to Na/K/2Cl cotransporter activity and back-leak of K⁺ into the lumen via ROMK (Fig. 23.2). This positive voltage difference facilitates paracellular movement of Mg²⁺. Inhibition of the Na/K/2Cl cotransporter by a loop diuretic diminishes Mg²⁺ reabsorption. A similar decrease in Mg²⁺ reabsorption is also observed with volume expansion.

Fig. 23.2

Cellular model for Mg²⁺ transport in the cortical thick ascending limb of Henle’s loop

The paracellular movement of Mg²⁺ is thought to be mediated by proteins of the claudin family of tight junction proteins. The important protein of the claudin family is paracellin 1 or claudin-16. Mutations of the gene encoding paracellin causes hypomagnesemia (discussed later).

Evidence also exists for active transport of Mg²⁺ in the cortical TALH. This mechanism has been suggested based on the observation that Mg²⁺ transport is stimulated by antidiuretic hormone (ADH) and glucagon without any change in the potential difference .

Mg²⁺ ions exit across the basolateral membrane by being actively extruded against their electrochemical gradient. Although the mechanisms have not been studied in epithelial cells, the existence of a Mg-ATPase that extrudes Mg²⁺ has been reported in other cells. Also, a Na/Mg exchanger has been demonstrated in erythrocytes (see Fig. 23.2).

Distal Convoluted Tubule (DCT)

As stated earlier, the DCT reabsorbs 5–10 % of Mg²⁺, and the transport is active and transcellular. Mg²⁺ transport from the lumen to the cell occurs via an epithelial Mg²⁺ channel called the TRPM6. The DCT determines the final urinary excretion of Mg²⁺, as no or very little reabsorption occurs beyond this segment. Several factors influence TRMP6 expression and activity, and thus influence urinary excretion of Mg²⁺ (Table 23.1).

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