Disorders of Magnesium: Hypomagnesemia


Cause

Mechanism

Decreased intake

Protein-calorie malnutrition

Poor Mg2+ intake

Starvation

Poor Mg2+ intake

Prolonged i.v. therapy without Mg2+

Poor Mg2+ intake

Chronic alcoholism

Possible mechanisms include: (1) poor dietary intake; (2) alcohol-induced renal Mg2+ loss; (3) diarrhea; and (4) starvation ketosis-induced renal Mg2+ loss

Decreased intestinal absorption

Prolonged nasogastric suction

Removal from saliva & gastric secretions

Malabsorption (nontropical sprue and steatorrhea)

Loss from intestine

Diarrhea

Loss from intestine

Intestinal and biliary fistulas

Loss from stool and urine

Excessive use of laxatives

Loss from stool due to diarrhea

Resection of small intestine

Defective Mg2+ absorption

Familial hypomagnesemia with secondary hypocalcemia

Mutation in intestinal TRPM6 gene

Increased urinary loss

Inherited disorders of TALH

 Familial hypomagnesemia with hypercalciuria and nephrocalcinosis

Mutations in CLDN 16 gene (claudin-16 or paracellin-1) of tight junction proteins

 Familial hypomagnesemia with hypercalciuria and nephrocalcinosis with ocular manifestation

Mutations in CLDN19 gene (claudin-19) of tight junction protein

 Disorders of Ca/Mg-sensing receptor

Inactivating mutations in TALH/DCT Ca/Mg-sensing receptor

 Bartter syndrome

Mutations in Na/K/2Cl, ROMK, CIC-Ka/Kb-Barttin

Inherited disorders of DCT

 Familial hypomagnesemia with secondary hypocalcemia

Mutations in TRPM6 gene

 Isolated recessive hypomagnesemia with normocalciuria

Mutations in epidermal growth factor (EGF) gene

 Isolated dominant hypomagnesemia with hypocalciuria

Mutations in FXYD2 gene encoding γ-subunit of Na/K-ATPase

Acquired causes other than drugs

Volume expansion

Increased GFR with increased Na+, water and Mg2+ excretion

Hypercalcemia

Increased Mg2+ excretion

Diabetic ketoacidosis

Increased Mg2+ excretion

Hyperaldosteronism

Increased Mg2+ excretion

Drugs

Diuretics

Osmotic, loop and thiazide diuretics

Renal Mg2+ wasting, inhibition of TRPM6 by thiazides

Antibiotics

Aminoglycosides

Activation of CaSR receptors & renal Mg2+ wasting

Amphotericin B

Renal Mg2+ wasting (unknown molecular mechanism)

Pentamidine

↓ Mg2+ reabsorption probably in DCT

Foscarnet

Complexes with Mg2+ and Ca2+. ? Fanconi syndrome

Antineoplastics

Cisplatin

Renal Mg2+ wasting

EGF receptor antagonist (Cetuximab)

Inhibits TRPM6 activity

Proton pump inhibitors

Possible mechanisms include: (1) decreased intestinal absorption due to achlorhydria; (2) increased intestinal secretion and loss in feces; (3) decreased intestinal TRPM6 activity because of inhibition of H/K-ATPase, and (4) decreased transport via paracellular pathway

Immunosuppressives

Cyclosporine & tacrolimus

Inhibits TRPM6 activity

Rapamycin

Renal Mg2+ wasting due to inhibition of Na/K/2Cl and TRPM6 activity

Miscellaneous

Hyperthyroidism

Cellular shift

Hungry bone syndrome

Uptake by bones following parathyroidectomy

Neonatal hypomagnesemia

Renal loss in diabetic pregnant mothers, use of stool softeners by pregnant mothers, malabsorption/or hyperparathyroidism in mothers




Some Specific Causes of Hypomagnesemia



Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis (FHHNC)






  • Inherited as an autosomal recessive disorder


  • Caused by loss-of-function mutations in the CLAN16 gene that encodes claudin-16 (paracellin-1) tight junction protein


  • Clinically characterized by hypomagnesemia , renal wasting of Mg2+ and Ca2+, nephrocalcinosis and renal failure (30 %)


  • Polyuria, polydipsia, and urinary tract infections are common


  • Treatment includes oral citrates, thiazide diuretics, and enteral Mg2+ salts


Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis with Ocular Manifestation






  • A subset of these patients demonstrates additionally ocular abnormalities, such as myopia, chorioretinitis, and nystagmus, and hearing impairment. Such patients have been shown to have mutations in CLAN19 gene encoding claudin-19 protein


  • Treatment is similar to that of FHHNC


Familial Hypomagnesemia with Secondary Hypocalcemia






  • Inherited as an autosomal dominant disorder


  • Caused by mutations in TRPM6 gene encoding the Mg2+ channel in DCT and intestine


  • Patients present with profound hypomagnesemia and generalized seizures during the first few months of life. Also, hypocalcemia is prominant


  • Treatment is i.v. Mg2+ infusion during seizure activity followed by life-long oral therapy


Isolated Dominant Hypomagnesemia with Hypocalciuria






  • Inherited as an autosomal dominant disorder


  • Caused by mutations in the FXYD2 gene that encodes γ-subunit of the Na/K- ATPase in DCT


  • Malfunction of Na/K-ATPase leads to intracellular accumulation of Na+ and inhibition of Mg2+ transport, resulting in hypomagnesemia


  • Clinical manifestations include generalized seizures, mental retardation with severe hypomagnesemia and hypocalciuria


  • Similar to Gitelman syndrome with respect to hypocalciuria, but hypokalemia and metabolic alkalosis are absent in this disorder


  • Occurs in infants and adults


Isolated Recessive Hypomagnesemia (IRH) with Normocalciuria






  • A rare disorder characterized by seizures and psychomotor retardation during childhood and mental retardation during adult life


  • Caused by the mutation in EGF gene encoding the pro-epidermal growth factor (pro-EGF), which is cleaved by proteases to EGF in the kidney. In normal DGT, EGF occupies its receptor and activates TRPM6 channel so that Mg2+ reaborption is increased


  • Mutations in pro-EGF gene prevents full EGF synthesis, leading to low TRPM6 activity and decreased Mg2+ reabsorption


  • Only hypomagnesemia is present. Ca2+ excretion is normal


Bartter and Gitelman Syndromes (see Chaps. 3 and 15)






  • Clinical and biochemical characteristics of some inherited hypomagnesemic disorders are shown in Table 24.2.




    Table 24.2
    Clinical and biochemical characteristics of inherited disorders of hypomagnesemia














































































    Disorder
    Onset
    Serum Mg2+

    Serum Ca2+

    Serum K+

    Urine Mg2+

    Urine Ca2+

    Blood pH
    Nephro-calcinosis
    Renal stones
    Clinical characteristics

    Familial hypomagnesemia with hypercalciuria and nephrocalcinosis
    Childhood/adult
    ↓
    N
    N
    ↑↑
    ↑↑
    N
    Yes
    Yes
    Polyuria, renal failure

    Familial hypomagnesemia with secondary hypocalcemia
    Infancy
    ↓↓
    ↓
    N
    ↑
    N
    N
    No
    No
    Tetany, seizures

    Isolated dominant hypomagnesemia with hypocalciuria
    Childhood
    ↓
    N
    N
    ↑
    ↓
    N
    No
    No
    Seizures, chondrocalcinosis

    Isolated recessive hypomagnesemia with normocalciuria
    Childhood
    ↓
    N
    N
    ↑
    N
    N
    No
    No
    Tetany, seizures

    Gitelman syndrome

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    Jun 20, 2017 | Posted by in NEPHROLOGY | Comments Off on Disorders of Magnesium: Hypomagnesemia

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