Inherited Disorders of Renal Magnesium Handling

The genetic basis and cellular defects of a number of primary magnesium wasting diseases have been elucidated over the past decade. This review correlates the clinical pathophysiology with the primary defect and secondary changes in cellular electrolyte transport.

The described disorders include (1) hypomagnesemia with secondary hypocalcemia, an early-onset, autosomal-recessive disease segregating with chromosome 9q12-22.2; (2) autosomal-dominant hypomagnesemia caused by isolated renal magnesium wasting, mapped to chromosome 11q23; (3) hypomagnesemia with hypercalciuria and nephrocalcinosis, a recessive condition caused by a mutation of the claudin 16 gene (3q27) coding for a tight junctional protein that regulates paracellular Mg2+ transport in the loop of Henle; (4) autosomal-dominant hypoparathyroidism, a variably hypomagnesemic disorder caused by inactivating mutations of the extracellular Ca2+ /Mg2+ -sensing receptor, Casr gene, at 3q13.3-21 (a significant association between common polymorphisms of the Casr and extracellular Mg2+ concentration has been demonstrated in a healthy adult population); and (5) Gitelman syndrome, a recessive form of hypomagnesemia caused by mutations in the distal tubular NaCl cotransporter gene, SLC12A3, at 16q13. The basis for renal magnesium wasting in this disease is not known. These inherited conditions affect different nephron segments and different cell types and lead to variable but increasingly distinguishable phenotypic presentations. No doubt, there are in the general population other disorders that have not yet been identified or characterized. The continued use of molecular techniques to probe the constitutive and congenital disturbances of magnesium metabolism will increase the understanding of cellular magnesium transport and provide new insights into the way these diseases are diagnosed and managed.

Control of magnesium homeostasis resides principally within the nephron of the kidney [1] . Approximately 80% of the total plasma magnesium (0.65 to 1.20 mM) is filtered through the glomerulus. Five to 15% of the ultrafiltrable magnesium is reabsorbed by the convoluted and straight portions of the proximal tubule. The cortical segment of the thick ascending limb of the loop of Henle plays a major role in the determination of magnesium reabsorption, as it accounts for approximately 70% of magnesium conservation (Figure 1) . Ten to 15% of the filtered magnesium is delivered distally from the loop of Henle, of which 70 to 80% is reabsorbed by the distal tubule. There is no evidence for significant magnesium absorption beyond the distal convoluted tubule so that it plays an important role in determining the final urinary excretion [1] . There are no reports of significant magnesium secretion in any of the tubule segments that compose the nephron, so that control of renal magnesium homeostasis involve changes in reabsorption. Overall, less than 5% of the filtered magnesium normally appears in the urine.

Figure 1. Summary of segmental magnesium absorption along the nephron.

The purpose of this review is to discuss the familial disorders of renal magnesium reabsorption that lead to urinary magnesium wasting. Inborn errors of renal magnesium handling tell us much about the mechanisms that the kidney normally uses to conserve magnesium. The genetic basis and cellular defects of a number of primary magnesium wasting diseases have been elucidated over the past decade, whereas others remain to be identified and there are undoubtedly others that have not yet been recognized. In this review, we attempt to correlate the clinical pathophysiology with the primary defect and secondary changes in cellular electrolyte transport. We begin, however, with a brief overview of normal renal magnesium handling; more detailed reviews have been published elsewhere [1] [2] .

Proximal Tubule

In the adult, the proximal tubule reabsorbs only 10% of the filtered magnesium, whereas the fractional reabsorption of sodium and calcium is normally in excess of 70% [1] . However, in the neonate, the proximal tubule reabsorbs approximately 70% of the filtered magnesium–similar to that for sodium and calcium [2] . Lelievre-Pegorier et al. [2] reported that the permeability of the proximal tubule changes during development so that less magnesium is reabsorbed in the proximal tubule of the adult. This maturation in segmental handling of magnesium must be taken into consideration when assessing renal magnesium handling in children relative to that in adults.

Loop of Henle

De Rouffignac and colleagues showed [3] that the cortical segment of the thick ascending limb (cTAL) reabsorbs approximately 70% of the filtered magnesium, whereas the medullary segment (mTAL) does not absorb magnesium. They further reported that transepithelial magnesium absorption is passive, moving from lumen to the interstitial space through the paracellular pathway (Figure 2) . This is consistent with the earlier observations of Shareghi and Agus [4] . The driving force for magnesium movement is the positive luminal transepithelial voltage [3] . Any influence that alters transepithelial voltage or the permeability of the paracellular pathway will alter magnesium reabsorption in the cTAL [3] . The voltage in the loop is determined by the rate of Na-K-Cl cotransport and active sodium absorption. Changes in their transport rates will affect the transepithelial voltage and thus magnesium absorption. The permeability of the paracellular pathway is determined by electrostatic charges of proteins that compose this route [1] . Although there seems to be some selectivity in the paracellular pathway, changes in permeability, i.e., proteins that compose the pathway, would be expected to alter sodium and calcium as well as magnesium [1] [3] [5] . Recently, a paracellular protein, “paracellin-1″ or “claudin 16,” has been identified in the TAL [6] . The claudin 16 gene encodes a protein of 305 amino acids that form the tight junction of the paracellular pathway. Simon and colleagues [6] proposed that claudin 16 is involved in controlling magnesium and calcium permeability of the paracellular pathway in the cTAL.

Figure 2. Schematic model of magnesium absorption in the cortical thick ascending limb (cTAL) of Henle’s loop. Magnesium reabsorption is passive and occurs through the paracellular pathway. Furosemide diminishes Mg2+ absorption by inhibiting the Na-Cl-K cotransporter and the transepithelial voltage. Peptide hormones such as parathyroid hormone (PTH), calcitonin, glucagon, and arginine vasopressin (AVP) enhance magnesium reabsorption in the cTAL by increases in the transepithelial voltage and magnesium permeability of the paracellular pathway [3] [4] . Claudin 16, a tight junction protein, is involved with paracellular permeability [6] . The extracellular Ca2+ /Mg2+ -sensing receptor (Casr) modulates Mg2+ transport through changes in transepithelial voltage and alteration of the permeability of the paracellular pathway [10] [11] . HHN, hypomagnesemia with hypocalciuria and nephrocalcinosis; ADH, autosomal dominant hypoparathyroidism; FHH, familial hypocalciuric hypercalcemia; NSHPT, neonatal severe hyperparathyroidism.

A large number of hormones stimulate magnesium reabsorption in the loop (Table 1) . All of these hormonal responses are mediated by changes in both transepithelial voltage and paracellular permeability [1] . As indicated by the diversity of the hormones, the responses are mediated by different receptor-signaling pathways that change transepithelial voltage and paracellular structure.

TABLE 1 — Coordinate controls of Magnesium transport in the loop of Henle and distal tubule

Thick Ascending Limb Distal Tubule
Peptide hormones
parathyroid hormone Increase (7) Increase (15)
calcitonin Increase (1) Increase (8)
glucagon Increase (7) Increase (8)
arginine vasopressin Increase (7) Increase (8)
beta-adrenergic agonists isoproterenol Increase (1) Increase (8)
Prostaglandins, PGE2 Decrease (8) Increase (16)
Insulin Increase (1) Increase (15)
Mineralocorticoids aldosterone Increase (18) Increase (8)
Vitamin D 1,25(OH)2 D3 ? Increase (8)
Magnesium restriction Increase (1) Increase (8)
Hypermagnesemia Decrease (8) Decrease (8)
Hypercalcemia Decrease (8) Decrease (8)
Extracellular volume expansion Decrease (1) Increase (1)
Metabolic acidosis Decrease (8) Decrease (8)
Metabolic alkalosis Increase (8) Increase (8)
Phosphate-depletion Decrease (8) Decrease (8)
Potassium-depletion Decrease (8) Decrease (8)
Diuretics
furosemide Decrease (8) No effect (8)
amiloride No effect (8) Increase (8)
chlorothiazide No effect (8) Increase (8)
The specific studies are referenced in the review articles[1] [8] .

Hypermagnesemia and hypercalcemia have long been known to cause an increase in urinary magnesium and calcium excretion [8] . Massry et al. [9] elevated serum magnesium levels in thyroparathyroidectomized dogs and determined the urinary magnesium excretion rates with elevated filtered magnesium. Using clearance studies, they showed that elevated filtered magnesium concentration was initially associated with increases in magnesium reabsorption until an apparent tubular reabsorptive maximum, Tm, was attained, beyond which any additional filtered magnesium was excreted in the urine. The cellular basis for these results is the extracellular Ca2+ /Mg2+ -sensing receptor (Casr) present in the basolateral membrane of the TAL that inhibits salt transport and passive Mg2+ and Ca2+ absorption [10] [11] . Although the apparent Tm has been used in the clinical assessment of renal magnesium conservation, it is not easily interpreted because it is a receptor-mediated, not a transport-dependent, phenomenon [12] . The magnesium-loading test is a more appropriate approach to assess magnesium balance [13] [14] .

A number of influences affect renal magnesium conservation, including metabolic acidosis, potassium depletion, and hypophosphatemia [8] . Although the cellular mechanisms are poorly understood, these influences alter passive magnesium reabsorption in the loop by changing the transepithelial voltage or the permeability of the paracellular pathway. Furosemide diminishes the luminal positive voltage by virtue of its effects on the Na-K-Cl cotransporter. Because of this, acute usage of furosemide leads to enhanced distal delivery and increased urinary magnesium excretion [8] . However, with chronic furosemide therapy, urinary excretion usually returns to near control levels. This is likely due to enhanced reabsorption in the proximal tubule, loop, and distal tubule. Thus, prolonged furosemide use does not often lead to renal magnesium wasting.

Distal Tubule

Magnesium transport within the distal convoluted tubule (DCT) is transcellular and active in nature (Figure 3) . Magnesium enters the cell through selective channels across the apical membrane, driven by the transmembrane negative electrical potential [8] . Magnesium entry across the apical membrane is the rate-limiting step in transepithelial reabsorption, and many of the hormonal and nonhormonal controls act at this site. Cellular Mg2+ is actively extruded at the basolateral membrane, possibly by a sodium-dependent exchange mechanism [8] .

Figure 3. Schematic model of magnesium absorption in the distal convoluted tubule (DCT). Conductive pathways and carrier-mediated transport are denoted by shaded arrows. Peptide hormones such as PTH, calcitonin, glucagon, and AVP enhance magnesium reabsorption in the DCT. The extracellular Casr modulates hormone-stimulated Mg2+ transport through Gi protein coupling [8] . The sites of the transport inhibitors thiazides and amiloride are indicated [8] . The basis of the primary inherited disorders hypomagnesemia with secondary hypocalcemia (HSH), infantile primary hypomagnesemia with autosomal-dominant inheritance, and infantile primary hypomagnesemia with autosomal-recessive inheritance is speculative.

A large number of influences regulate magnesium transport within the DCT (Table 1) . Most of these controls are similar to those of the TAL. However, the cellular mechanisms are different, as the influences within the DCT act through changes in active magnesium transport. Renal cells respond very sensitively to decreased magnesium availability caused by dietary restriction, intestinal malabsorption, or excessive renal excretion by increasing transport rates [8] . The change in magnesium transport is rapid, sensitive, and selective for magnesium. This response is a genomic effect involving transcriptional/translational control and de novo protein synthesis, possibly by the formation of new transporters or channels [1] . This adaptive response of transport rates in the DCT provides for the selective renal magnesium conservation. Elevated extracellular Mg2+ or Ca2+ inhibits fractional magnesium transport in superficial rat distal tubules through activation of the Casr [17] . These studies clearly indicate that hypermagnesemia and hypercalcemia per se can modify hormone regulation of magnesium transport within the distal tubule, leading to increased urinary magnesium excretion. Metabolic acidosis, hypokalemia, and phosphate depletion inhibit active Mg2+ transport in the DCT [8] . Experimental and clinical data suggest an association among these diseases [18] . Our evidence indicates that these three influences have different actions on cellular magnesium transport so that the three disturbances may act in an additive manner to compromise renal magnesium conservation.

The distal diuretics amiloride and chlorothiazide increase Mg2+ transport in DCT cells [8] . Although amiloride has clearly been shown to be a magnesium-sparing diuretic, chronic chlorothiazide usage may lead to renal magnesium wasting [8] . The cellular mechanisms for the chronic chlorothiazide effects are unclear but may involve hypokalemia, which can jeopardize renal magnesium conservation [8] .

Inherited Disorders of Renal Magnesium Handling

Primary Inherited Disorders of Renal Magnesium Handling

A number of inherited magnesium wasting diseases that likely have their basis in defective magnesium transporters have been described (Table 2) .

TABLE 2 — Inherited disorders of renal magnesium handling

Primary inherited disorders of renal magnesium handling
  • hypomagnesemia with secondary hypocalcemia
  • infantile primary hypomagnesemia with autosomal dominant inheritance
  • infantile primary hypomagnesemia with autosomal recessive inheritance
Other inherited disorders
  • idiopathic hypermagnesiuria
  • congenital hypomagnesemia not yet classified
Hypomagnesemia associated with hypercalciuria and nephrocalcinosis
  • hypomagnesemia with hypercalciuria and nephrocalcinosis
Inherited disorders associated with abnormal extracellular Mg2+ /Ca2+ sensing
  • autosomal dominant hypoparathyroidism
  • familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism
Hypomagnesemia associated with abnormal renal NaCl transport
  • Gitelman syndrome
  • Bartter syndrome

Hypomagnesemia with Secondary Hypocalcemia.

Hypomagnesemia with secondary hypocalcemia (HSH) is an autosomal-recessive disorder that manifests in the newborn period and is characterized by very low serum magnesium and low calcium concentrations [19] [20] [21] [22] [23] [24] (Table 3) . Patients usually present before 6 mo of age with neurologic symptoms of hypomagnesemic hypocalcemia, including tetany, muscle spasms, and seizures [25] [26] . In older children with inadequate magnesium control, clouded sensorium and disturbed speech are often seen and choreoathetoid movements have been described. The hypocalcemia is secondary to parathyroid failure and peripheral parathyroid hormone (PTH) resistance as a result of magnesium deficiency [27] . Hypokalemia is occasionally present and is corrected only with normalization of plasma magnesium [28] .

TABLE 3 — Clinical features in different inherited forms of hypomagnesemia a
Feature Hypomagnesemia and Secondary Hypocalcemia Isolated Dominant Hypomagnesemia (Infantile) Isolated Recessive Hypomagnesemia (Infantile)
Inheritance AR AD AR
Gene ? ? ?
Chromosome 9q12-22.2 11q23 ?
Serum Mg2+
Serum K+ N N N
Serum Ca2+ N N
Blood pH N N N
Urine K+ N N ?
Urine Mg2+ N or
Urine Ca2+ N or ?
Onset Neonatal Childhood Childhood
Growth N N ?
Rickets - - -
Chrondrocalcinosis - + ?
Other abnormalities - (Seizures) -
OMIM# 602014 154020 248250
Feature Hypomagnesemia, Hypercalciuria, and Nephrocalcinosis Autosomal Dominant Hypoparathyroidism
Inheritance AR AD
Gene PCLN1 Casr
CLDN16
Chromosome 3q27 3q13.3-21
Serum Mg2+ or N
Serum K+ N N
Serum Ca2+ N
Blood pH N or sl. N
Urine K+ ?N N
Urine Mg2+
Urine Ca2+
Onset Infancy Infancy
Growth N
Rickets + -
Chrondrocalcinosis - +
Other abnormalities Ocular anomalies -
OMIM# 603959 601198
601199
Feature Gitelman Bartter 1 Bartter 2 Bartter 3 Bartter 4
Inheritance AR AR AR AR AR
Gene SLC12A3 NKCC2 ROMK1 ClCNKB ?
Chromosome 16q13 15q15-21 11q24 1p36 1p31
Serum Mg2+ ?N ?N ?N N
Serum K+
Serum Ca2+ N N or N N N
Blood pH
Urine K+
Urine Mg2+ ? ? ? ?
Urine Ca2+ N or sl.
Onset Childhood Infancy or antenatal Antenatal Variable Antenatal
Growth
Rickets ++ - - - -
Chrondrocalcinosis ++ + ?+ - ?+
Other abnormalities (Empty sella) - - - Sensorineural deafness
OMIM# 263800 241200 600359 602023 602522
600968 600839 601678

a AR, autosomal recessive; AD, autosomal dominant; , increased; , markedly increased; sl., slightly increased; N, normal; +, present; -, absent; other abnormalities in parentheses are atypical features; OMIM# refers to the Online Mendelian Inheritance in Man database reference number (http://www3.ncbi.nlm.nih.gov/omim/)

The disease primarily is due to defective intestinal magnesium absorption and may be fatal unless treated with high oral intakes [19] [20] [29] [30] [31] . Walder et al. [32] reported that HSH is an autosomal recessive disease and showed by genetic linkage studies that the gene segregates to chromosome 9 (9q12-9q22.2) (Table 3) . They suggested that the candidate gene codes for a receptor or ion channel involved in active intestinal magnesium absorption. As passive intestinal transport is normal, the disease can be controlled with high oral magnesium supplements, although the acute presentation may be more rapidly corrected with intramuscular or intravenous magnesium therapy. Renal magnesium conservation has been reported to be normal in most studies, suggesting that the kidney responds appropriately to low circulating magnesium levels by reabsorbing fractionally greater amounts of filtered magnesium. In some cases, however, there may be a renal leak, which manifests in the inability of oral supplements to normalize sufficiently the serum magnesium or the hypomagnesemic symptoms [33] . We speculate that the renal leak may be due to altered Mg2+ entry into DCT cells (Figure 3) . Although intramuscular or intravenous magnesium supplementation may be required, continuous nocturnal nasogastric infusion of magnesium may be an effective alternative [34] . Whether HSH is genetically heterogeneous remains to be seen, but additional studies to address renal tubular magnesium absorption as a function of plasma concentration and filtered magnesium in patients with well-delineated intestinal defects clearly are warranted.

Infantile Isolated Renal Magnesium Wasting (Dominant).

Hypomagnesemia as a result of isolated renal magnesium loss is an autosomal-dominant condition associated with few symptoms other than chondrocalcinosis [35] . Patients always have hypocalciuria and variable but usually mild hypomagnesemic symptoms [36] . Meij et al. [37] reported that the disorder maps to chromosome 11q23 in two large Dutch families. Database searches of the linkage region have failed to identify candidate genes, but Meij et al. speculated, from our experimental studies, that the mutation may lie in the distal tubule (Figure 3) [8] [37] .

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