MAGNESIUM ABSORPTION Intestinal magnesium absorption

Mg²⁺ is mainly absorbed in the small bowel (jejunum and ileum) with some absorption occurring in the colon [23, 24]. Under physiological conditions, approximately 30%

to 40% of orally ingested Mg²⁺ is absorbed [25]. However, the amount absorbed from the bowel can increase to 80%

in the presence of deficiency. Mg²⁺ absorption occurs via  two different pathways: a saturable, active trans­

cellular transport and a nonsaturable passive paracellular pathway  [26]. At low intraluminal concentrations, Mg²⁺

is  primarily absorbed via the active transcellular route whereas with rising intraluminal concentrations the passive paracellular pathway gains importance. The satu­

ration kinetics of the transcellular pathway indicate a limited active transport capacity. The two transport sys­

tems together yield a curvilinear kinetic of transepithelial

Mg²⁺ transport. The  defect in intestinal Mg²⁺ absorption observed in children with TRPM6 defects (see later) points to a critical role of this apically located Mg²⁺‐permeable ion channel for active transcellular Mg²⁺ absorption.

Renal magnesium conservation

Following absorption from the bowel, Mg²⁺ enters the blood stream and is filtered within the renal glomeruli.

Approximately 95% to 99% of filtered Mg²⁺ is reabsorbed along the kidney tubule [27] so that under physiological, normomagnesemic conditions, 3% to 5% of filtered Mg²⁺

is finally excreted in the urine. The mechanisms of transepithelial Mg²⁺ transport along the kidney tubule significantly vary depending on the different tubular seg­

ments involved.

A minor portion (15% to 20%) of filtered Mg²⁺ is already reabsorbed in the proximal convoluted tubule (PCT).

Interestingly, this nephron segment is capable of reab­

sorbing up to 70% of filtered Mg²⁺ in the neonate. The increased paracellular permeability of the PCT for Mg²⁺

responsible for this phenomenon disappears with matu­

ration of this tubular segment [28].

The vast majority of filtered Mg²⁺ (~70%) is reabsorbed in the thick ascending limb of Henle`s loop (TAL). Mg²⁺

reabsorption in the TAL is passive and paracellular in nature and occurs together with calcium through special­

ized tight junctions. These tight junctions are composed of a specific set of proteins of the claudin family that, on one hand, seal the paracellular space for water and elec­

trolytes, but, on the other hand, allow for the selective passage of ions. In the TAL, tight junctions are formed, amongst others, by the claudin proteins claudin‐16 and claudin‐19 that play a key role in regulating paracellular Ca²⁺ and Mg²⁺ transport [29]. Mutations affecting these two proteins result in impaired paracellular reabsorption of both Ca²⁺ and Mg²⁺ causing familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) [30].

Affected patients exhibit hypomagnesemia and develop nephrocalcinosis in childhood caused by the presence of  hypercalciuria [31]. Unfortunately, patients almost uniformly develop chronic renal failure mainly in the second decade of life [32].

Paracellular Ca²⁺ and Mg²⁺ transport in the TAL is regu­

lated by the action of the basolaterally located calcium sensing receptor (CaSR). The CaSR senses extracellular Ca²⁺ as well as Mg²⁺concentrations in the distal nephron as well as in other tissues and thereby plays an essential role in Ca²⁺ and Mg²⁺ homeostasis [33]. Concerning renal tubular magnesium handling, PTH not only increases Mg²⁺ reabsorption in the cortical TAL by enhancing para­

cellular permeability, but also increases transcellular Mg²⁺ reabsorption in the DCT [34, 35].

In the parathyroid, the CaSR is responsible for adjusting the rate of PTH synthesis and release to the extracellular levels of Ca²⁺ and Mg²⁺. The CaSR bears multiple low‐

affinity cation binding sites in its extracellular domain allowing for a cooperative interaction with multiple

cations in a millimolar concentration range [36]. Therefore, Mg²⁺ and Ca²⁺ are both able to activate the CaSR and affect  PTH synthesis and secretion [34]. In addition, intracellular Mg²⁺ is involved in the activation of adenylate cyclase and in intracellular signaling of cyclic AMP [37].

Activation of the CaSR by Mg²⁺ results in stimulation of phospholipase C and A2 and inhibition of cellular cAMP with inhibition of PTH release [38]. In the kidney, CaSR activation decreases paracellular sodium, calcium, and magnesium transport, resulting in a renal loss of these cations. Hereditary disorders may result from either acti­

vating or inactivating CaSR mutations. Heterozygous, activating mutations lead to autosomal‐dominant hypoc­

alcemia (ADH). Patients may present with hypocalcemic cerebral seizures or muscle spasms. Inappropriately low PTH levels (caused by activation of the CaSR in the parathyroid gland) lead to the diagnosis of primary hypoparathyroidism. The hypocalcemia is associated with hypomagnesemia in a significant number of affected patients [39]. In addition, patients may develop a clinically relevant degree of renal salt and water losses caused by inhibition of active transcellular NaCl reabsorption in the TAL that is reflected by a laboratory profile similar to Bartter syndrome [19].

Inactivating mutations on one or two alleles lead to familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism (NSHPT), respectively. Serum PTH levels are inappropriately high and renal Ca²⁺ and Mg²⁺

excretions are markedly reduced. In addition to sympto­

matic hypercalcemia, patients with NSHPT also exhibit mild hypermagnesemia [20].

Although only 5–10% of filtered Mg²⁺ is reabsorbed in the distal convoluted tubule (DCT), active transcellular Mg²⁺

transport in this segment is of critical importance for deter­

mining the final urinary Mg²⁺ excretion because there is no significant Mg²⁺ transport in the collecting duct [30, 40].

Though transepithelial magnesium transport in the DCT is far from being completely understood, molecular genetic studies in patients with different forms of heredi­

tary hypomagnesemia have provided critical insight into the mechanisms and regulation of underlying transport processes.

Molecular genetic studies in patients with hypomagne­

semia with secondary hypocalcemia lead to the identification of TRPM6 as a critical component of active transcellular Mg²⁺

transport in intestine and kidney [12, 13]. TRPM6 is thought to be involved in the formation of apically‐located Mg²⁺

permeable ion channels. Through these ion channels, Mg²⁺

enters the epithelial cell driven by the membrane potential.

Recessive loss of function mutations in TRPM6 result in the  development of severe hypomagnesemia and cerebral seizures during infancy. In addition to hypomagnesemia, patients also display suppressed PTH levels and consecutive hypocalcemia. The suppression of PTH is thought to result from a block of PTH synthesis and secretion in the presence of profound hypomagnesemia [41]. This paradoxical inhibi­

tion of the parathyroid involves intracellular signaling pathways of the CaSR with an increase in the activity of inhib­

itory G alpha subunits [42].

In addition, PTH‐induced release of Ca²⁺ from bone is substantially impaired in hypomagnesemia [21, 22, 43].

Intracellular Mg²⁺ is a cofactor of adenylate cyclase and decreases in intracellular ionized Mg²⁺ result in a resist­

ance to PTH [44–46]. The hypocalcemia is resistant to treatment with Ca²⁺ or vitamin D, but rapidly responds to Mg²⁺ supplementation.

Unfortunately, the molecular nature of basolateral Mg²⁺ export is still unknown. However, a number of molecular studies in patients with rare forms of heredi­

tary hypomagnesemia could show that the transcellular transport of Mg²⁺ in the DCT is highly dependent on membrane potential and cellular energy content. Examples are a dominant negative mutation in the gamma subunit of basolateral Na‐K‐ATPase that physiologically influ­

ences the affinities for sodium and ATP [47] or mutations in KCNA1 encoding the Kv1.1 potassium channel thought to be involved in the generation of the apical membrane potential in DCT cells [48].

A more recent study identified mutations in a trans­

membrane protein, CNNM2 (cyclin M2), that potentially represents a basolaterally expressed sensor for interstitial Mg²⁺ concentrations [49]. Finally, Mg²⁺ transport in the DCT was found to be hormonally regulated by EGF (epi­

dermal growth factor) that acts via basolaterally located receptors [50]. A mutation disrupting the basolateral sort­

ing of this EGF receptor leads to impaired membrane traf­

ficking of TRPM6, which finally results in reduced Mg²⁺

reabsorption [49].

Besides these hereditary disorders leading to renal Mg²⁺

wasting, hypomagnesemia may be a result of a number of diverse clinical conditions and also a clinically relevant side effect of a multitude of medical treatments: polyuria per se may result in decreased renal tubular reabsorption of Mg²⁺. Diuretics, antibiotics, calcineurin inhibitors, and epi­

dermal growth factor receptor antagonists may also decrease renal tubular reabsorption of Mg²⁺ [4]. These drugs have been shown to downregulate renal Mg²⁺ transport proteins including TRPM6 ion channels in the DCT and thereby induce urinary magnesium losses [21, 22, 43].

Deficiencies in intracellular Mg²⁺ may develop in the presence of a normal serum Mg²⁺ [51, 52]. Intracellular Mg²⁺ may be a key regulator of serum PTH [3].

CONCLUSION

Ca²⁺ and Mg²⁺ homeostases are closely linked. Our understanding of Mg²⁺ homeostasis has significantly advanced by increased understanding of the pathophysiol­

ogy of inherited disorders resulting in hypomagne­

semia (Table 23.1). Hypomagnesemia in turn can result in hypocalcemia and requires careful assessment and correction in order to normalize serum Ca²⁺. Our under­

standing of the hormonal regulation of Mg²⁺ is still incom­

plete and is an area of active research. Mg²⁺ homeostasis is maintained by the bowel, kidney, and bone and is essen­

tial for cardiovascular, neuromuscular, and skeletal health.

176 Magnesium Homeostasis

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Table 23.1. Inherited disorders of magnesium homeostasis.

Disorder Inheritance Genetic Abnormality Clinical Features

Hypomagnesemia with secondary hypocalcemia (HSH)

Autosomal recessive TRPM6 (transient receptor

potential cation channel) Severe hypomagnesemia with hypocalcemia;

hypoparathyroidism, and neurological symptoms of seizures, tetany, or muscle spasm Familial hypomagnesemia

with hypercalciuria and nephrocalcinosis (FHHNC)

Autosomal recessive CLDN16, CLDN19 Renal Ca²⁺ and Mg²⁺ wasting, polyuria/polydipsia, cramps, tremors, and convulsions; renal impairment

Autosomal dominant hypoparathyroidism (ADH)

Autosomal recessive CASR (Ca²⁺­sensing receptor,

CaSR) Hypocalcemia, hypomagnesemia

Gitelman syndrome Autosomal dominant SLC12A3 (sodium chloride

cotransporter (NCC)) Hypokalemic alkalosis, secondary hyperaldosteronism,

hypomagnesemia, and hypocalciuria

EAST (epilepsy, ataxia, sensorineural deafness, and renal tubulopathy) syndrome

Autosomal recessive KCNJ10 (Kir4.1 K⁺­channel) Salt wasting, hypomagnesemia, epilepsy, ataxia, sensorineural deafness, mental retardation Isolated dominant

hypomagnesemia Autosomal

dominant, de novo FXYD2 (Na/K­ATPase gamma

subunit) Hypomagnesemia, seizures,

hypocalciuria HNF1B (hepatocyte nuclear

factor 1 beta) HNF1b nephropathy, MODY 5 diabetes, hypomagnesemia CNNM2 (cyclin M2) Hypomagnesemia, seizures,

intellectual disability KCNA1

(Kv1.1, K⁺­channel) Muscle cramps, tetany, muscle weakness, tremor,

hypomagnesemia Isolated recessive

hypomagnesemia Autosomal recessive EGF (epidermal growth factor) Hypomagnesemia, seizures