Medical Physiology, 3rd Edition


Most Mg2+ reabsorption takes place along the TAL

Approximately 99% of the total body stores of magnesium reside either within bone (~54%) or within the intracellular compartment (~45%), mostly muscle. Renal magnesium excretion plays an important role in maintaining physiological plasma magnesium levels. The body maintains the total magnesium concentration in blood plasma within narrow limits, 0.8 to 1.0 mM (1.8 to 2.2 mg/dL). Of this total, ~30% is protein bound (Table 36-8). The remaining ~70% of total magnesium, which is filterable, is made up of two components. Less than 10% is complexed to anions such as phosphate, citrate, and oxalate, thus leaving ~60% of the total as free, ionized magnesium (Mg2+).

TABLE 36-8

Components of Total Plasma Magnesium





Ionized Mg2+




Diffusible magnesium complexes




Nondiffusible (protein-bound) magnesium




Total magnesium




Disturbances of Mg2+ metabolism usually involve abnormal losses, and these occur most frequently during gastrointestinal malabsorption (see p. 939) and diarrhea, in the course of renal disease, and following the administration of diuretics. Clinical manifestations of Mg2+ depletion include neurological disturbances such as tetany (especially when associated with hypocalcemia), cardiac arrhythmias, and increased peripheral vascular resistance. Conversely, increased Mg2+ intake may lower blood pressure and may reduce the incidence of hypertension. Severe hypermagnesemia, which may occur following excessive intake or renal failure, results in a toxic syndrome involving nausea, hyporeflexia, respiratory insufficiency, and cardiac arrest.

Normally, 5% or less of the filtered magnesium load appears in the urine (Fig. 36-17A). In contrast to the predominantly “proximal” reabsorption pattern of the major components of the glomerular filtrate, Mg2+ reabsorption occurs mainly along the TAL.


FIGURE 36-17 Magnesium handling by the kidney. In A, the numbered yellow boxes indicate the fraction of the filtered load that various nephron segments reabsorb. The green boxes indicate the fraction of the filtered load that remains in the lumen at various sites. The values in the boxes are approximations. CCT, cortical collecting tubule; ICT, initial collecting tubule; OMCD, outer medullary collecting duct; PCT, proximal convoluted tubule; PST, proximal straight tubule.

Normally, the proximal tubule reabsorbs only ~15% of the filtered magnesium load (see Fig. 36-17B). Water reabsorption along the proximal tubule causes luminal [Mg2+] to double compared with the value in Bowman's space, thereby establishing a favorable Mg2+ electrochemical gradient for passive, paracellular Mg2+ reabsorption. Solvent drag may also contribute to the paracellular reabsorption of Mg2+. Because proximal paracellular permeability to Mg2+ is significantly less than that to Ca2+, Mg2+ reabsorption is not as sensitive to changes in extracellular volume as is Ca2+ reabsorption.

The TAL absorbs ~70% of the filtered magnesium load (see Fig. 36-17C). The driving force for paracellular Mg2+ reabsorption is the lumen-positive voltage of the TAL (see p. 758).

In the TAL, the tight-junction proteins claudin 16 and claudin 19 (see pp. 43–44) account for the high paracellular cation permeability that is necessary for paracellular Mg2+ reabsorption. Mutations of CLDN16 or CLDN19 genes cause an autosomal recessive disorder of severe renal Mg2+ wasting with hypomagnesemia.

Mg2+ reabsorption along the DCT, which is predominantly transcellular (see Fig. 36-17D), accounts for only ~10% of the filtered load. Mg2+ entry across the apical membrane may take place via the TRPM6 cation channel (see Table 6-2, family No. 5). Because both luminal and intracellular Mg2+ are in the millimolar range, the key driving force is the inside-negative membrane potential. The efflux of K+ through apical Kv1.1 K+ channels neutralizes the entry of positive charge via Mg2+ uptake. The mechanism of Mg2+ extrusion across the basolateral membrane may be secondary active transport by Na-Mg exchange (SLC41A1). imageN36-15


Regulation of Magnesium Reabsorption in the DCT

Contributed by Gerhard Giebisch, Erich Windhager, Peter Aronson

Active Mg reabsorption is tonically stimulated by the epidermal growth factor receptor (EGFR). Identification of patients with syndromes including renal Mg wasting and hypomagnesemia due to mutations in TRPM6, Kv1.1, and EGF support this model. In addition, renal Mg wasting due to mutations in the Na/Cl cotransporter, the γ subunit of the Na-K pump, the transcription factor HNF1B that affects γ subunit expression, or the basolateral K+ channel Kir 4.1/5.1 suggest that these processes are also required for normal Mg reabsorption.

Mg2+ reabsorption increases with depletion of Mg2+ or Ca2+, or with elevated PTH levels

Table 36-9 shows the site of action of factors modulating renal Mg2+ excretion.

TABLE 36-9

Factors Affecting Mg2+ Reabsorption Along the Nephron imageN36-17




Proximal tubule

Volume contraction

Volume expansion


PTH, calcitonin, glucagon, AVP

Low plasma [Mg2+]

Metabolic alkalosis

Furosemide and related loop diuretics


High plasma [Mg2+] or [Ca2+]


PTH, calcitonin, glucagon, estrogens, vitamin D

Metabolic alkalosis

Low plasma [Mg2+]


High plasma [Mg2+] or [Ca2+]

Metabolic acidosis

K+ or phosphate depletion


Regulation of Mg2+ Reabsorption

Contributed by Gerhard Giebisch, Erich Windhager

In addition to the factors discussed beginning on page 791, other factors modulate the handling of Mg2+, of which we discuss two.

Effective Circulating Volume

As is true for Ca2+, a decrease in effective circulating volume leads to an increase in Na+ reabsorption and an increase in the forces that drive Mg2+ reabsorption via paracellular pathways. Thus, volume contraction increases Mg2+ reabsorption, whereas volume expansion has the opposite effect.

Acid-Base Balance

As is the case for Ca2+, alkalosis increases Mg2+ reabsorption. However, for Mg2+, the effect is at the level of the TAL.

Mg2+ Depletion

In response to low plasma [Mg2+], the kidney reduces fractional excretion of Mg2+ to very low levels (<2%). This adaptive response is due to upregulation of Mg2+ reabsorption in the TAL and DCT.

Hypermagnesemia and Hypercalcemia

The kidney seems to discriminate poorly between increases in plasma [Mg2+] and [Ca2+]. Thus, each of these disturbances inhibits the reabsorption of both Mg2+ and Ca2+ in the TAL, thereby leading to increased urinary excretion of both Mg2+ and Ca2+. It is thought that high plasma [Mg2+] and [Ca2+] each diminish Mg2+ reabsorption because each cation can bind to the CaSR.


PTH is the most important hormone for Mg2+ regulation, increasing distal Mg2+ reabsorption. When tested separately in hormone-depleted animals, AVP, glucagon, and calcitonin all stimulate Mg2+ reabsorption in the TAL, acting via cAMP and PKA. Many of these hormones probably act by modulating passive Mg2+ movement through the paracellular pathway, either by changing NaCl transport and transepithelial voltage or by increasing paracellular permeability.


In general, diuretics decrease Mg2+ reabsorption and thus enhance Mg2+ excretion. Loop diuretics have effects on Mg2+ similar to those on Ca2+ and act by depressing the lumen-positive voltage in the TAL and thus the gradient for passive, paracellular Mg2+ reabsorption. Osmotic diuretics, such as mannitol, also reduce Mg2+ reabsorption along the loop of Henle. Thiazide diuretics reduce Mg2+ reabsorption in the DCT, at least in part by indirectly downregulating expression of TRPM6 Mg2+ channels.