Inherited Disorders of Renal Magnesium Handling

Infantile Isolated Renal Magnesium Wasting (Recessive).

There is evidence for a variant form of hypomagnesemia that is more consistent with isolated renal magnesium loss with autosomal-recessive inheritance. Meij et al. excluded linkage to any known previously reported loci indicating a distinct disease (I.C. Meij, personal communication, April 1999). The patients also have variable symptoms, but they usually have normal urinary calcium excretion [38] [39] . Because the epithelial transporters of magnesium have not been conclusively delineated, it is unclear at what level the tubule magnesium absorption is affected.

Because both dominant and recessive inheritance have been reported, it is likely that a number of familial renal magnesium wasting diseases exist. As the distal tubule reabsorbs 10 to 15% of the filtered magnesium (80 to 95% of that delivered to it), one would expect that if the primary reabsorptive channel were affected, then renal magnesium conservation would be severely compromised and lead to marked hypomagnesemia. Alternatively, there may be separate magnesium transporters within the distal tubule under separate genetic control. This is a fertile ground for further genetic studies.

Idiopathic Hypermagnesiuria

Although idiopathic hypercalciuria is an established clinical entry, the notion that a similar state of idiopathic hypermagnesiuria may occur in some fraction of the general population has not been examined extensively. The calcium-losing state is a familial disorder associated with increased urinary calcium oxalate and calcium hydrogen phosphate supersaturation, frequently leading to stone formation [40] . Current evidence is that this disease is genetic in origin [41] . By selective inbreeding, Bushinsky [40] was able to establish a colony of hypercalciuric stone-forming rats. These animals routinely develop kidney stones on normal dietary calcium intake. In rats, the stones are more likely to be brushite (calcium hydrogen phosphate) then calcium oxalate, which is more common in humans. The magnesium content of the stones is not elevated, and abnormal renal magnesium handling is not thought to be part of the condition. Bushinsky and colleagues showed that the defects that lead to hypercalciuria include increased intestinal calcium absorption and bone resorption associated with increased intracellular vitamin D receptor concentrations [40] . The molecular links to the associated defect of renal calcium reabsorption are still the subject of intense investigation [42] . On the basis of responses to furosemide and chlorothiazide, these investigators suggested that the renal defect is localized to the TAL of the loop of Henle [42] , but the molecular basis of the inherited defect is not known [42] . Because the rats have normal renal magnesium homeostasis, it is reasonable to conclude that the defect is located more distally where calcium and magnesium are separately controlled [8] .

An increasingly popular approach to the genetics of disease is the identification of candidate loci for quantitative traits. Like height or arterial BP, serum and urine magnesium concentrations lie along a continuum and can be analyzed as quantitative traits (Figure 4) . Genetic studies of quantitative traits are difficult to perform because family members usually cannot be divided neatly into affected and unaffected categories as can be done with mendelian (single gene) disorders. Moreover, most quantitative traits are specified by more than one gene (polygenic inheritance), resulting in the failure of traditional linkage analysis to detect the effects of any single locus without prohibitively large population sampling. In an effort to define the genetic basis of magnesium homeostasis, Henrotte and colleagues [43] established inbred lines of mice by selecting for high and low plasma magnesium levels. Mice of the hypomagnesemic line have inappropriately high urinary magnesium excretion relative to the extracellular levels [44] . The hypomagnesemic, hypermagnesiuric mice have normal calcium homeostasis, suggesting a selective tubular defect of magnesium reabsorption. Genetic analysis of these mice indicated that both histocompatibility (H2)-related and H2-unrelated to loci were significant determinants of extracellular and intracellular magnesium content in the mice [44] . The hypomagnesemic, hypermagnesiuric mice have normal calcium homeostasis, suggesting a locus controlling a selective tubular pathway of magnesium reabsorption. Parallel studies in humans are sparse. Classically, comparison of monozygotic with dizygotic twins has been a useful measure of genetic contributions to the variability of quantitative traits, although the results frequently are subject to overinterpretation. Analysis by Henrotte indicates that serum magnesium is a genetic trait [45] , a conclusion further supported by quantitative analysis of sib-pair data [46] . No human locus has been clearly implicated as a determinant of magnesium homeostasis, but common functional polymorphisms of those genes whose complete loss causes inherited hypomagnesemia are obvious possibilities. We recently described strong associations between the common polymorphism of the Casr gene and extracellular calcium concentrations [47] [48] , making it an attractive candidate in this regard.

Figure 4. (A) A histogram and best-fit gaussian curve of total serum magnesium for 389 women between 18 and 35 yr of age. (B) The same data after correction for serum albumin. Note that the mean (0.772 mmol/L) is unchanged but the SD decreases from 0.58 to 0.48 mmol/L with the correction. Because serum albumin concentrations themselves may be genetically determined, it becomes clear that any genetic analysis of total serum magnesium might identify genes that regulate albumin and have nothing to do with magnesium homeostasis per se. Even for albumin-corrected magnesium, other co-determinants of the circulating magnesium pool may be confounders. With ionized magnesium, covariation with blood pH represents another confounding covariate. Thus, any genetic analysis of serum magnesium as a quantitative trait requires careful consideration of the quantity being measured.

Clinically, such genetic determinants should be useful in the delineation of gene-environment interactions in diseases characterized by abnormalities of magnesium homeostasis [49] . For example, in the presence of a genetic polymorphism that predisposes to enhanced renal magnesium conservation and elevated resting blood level, a patient may be more likely to experience toxic effects of magnesium administration–during tocolytic therapy, for example. Conversely, an individual with a polymorphism that predisposes to increased renal magnesium loss and lower blood levels may be abnormally sensitive to the hypomagnesemic effects of drugs or to the hypomagnesemic states induced by alcoholism or diabetes. Thus, genetic analysis of magnesium concentration as a quantitative trait will benefit from and probably contribute to our understanding of the less common inherited disorders that cause hypomagnesemia, as well as the more common acquired conditions characterized by low magnesium or renal magnesium wasting.

Hypomagnesemia with Hypercalciuria and Nephrocalcinosis

A distinct syndrome of hypomagnesemia with hypercalciuria and nephrocalcinosis (HHN) has been described. The HHN syndrome is an autosomal-recessive disorder that is characterized by renal magnesium wasting resulting in persistent hypomagnesemia, marked hypercalciuria leading to early nephrocalcinosis [50] [51] [52] [53] [54] [55] . It is distinguished from other conditions by the absence of infantile hypocalcemic tetany and normal plasma potassium [52] . Also characteristic is the multisystem involvement; the most distinctive features are ocular abnormalities including severe myopia, nystagmus, and chorioretinitis. Hearing impairment, tetany, seizures, chondrocalcinosis, rickets, arterial hypertension, and gouty arthritis all have been reported [52] [53] . The hypomagnesemia is unresponsive to magnesium administration. Renal transplantation corrects the abnormal magnesium and calcium handling and normalizes serum magnesium and calcium [53] . Rodriguez-Soriano et al. [56] postulated that absorption of magnesium and calcium in the loop of Henle is abnormal because chlorothiazide corrects the hypercalciuria, although it was only variably effective in raising the plasma magnesium. Using positional cloning, Simon et al. [6] identified a human gene, claudin 16 (CLDN16; paracellin-1 [PCLN-1]). that codes for a tight junctional protein located in the paracellular pathway of the TAL. Mutations in this gene presumably result in abnormal permeability of the paracellular pathway leading to decreased magnesium and calcium reabsorption (Figure 2) . The marked increase in urinary calcium predisposes to renal stone formation and its sequelae. Accordingly, these patients may require early transplantation.

Inherited Disorders Associated with Abnormal Extracellular Mg2+ /Ca2+ Sensing

Autosomal Dominant Hypoparathyroidism.

The Casr plays an important role in controlling calcium and magnesium transport in both the loop and the distal tubule [10] [17] . Both activating and inactivating mutations of the Casr have been described and are now well characterized [57] . Activating mutations (autosomal dominant hypoparathyroidism) are dominant and present clinically as isolated hypocalcemic hypoparathyroidism. Associated hypomagnesemia may be observed in up to half of the patients [58] [59] . Because the mutant parathyroid and kidney Casr has a lower set-point for plasma Ca2+ and Mg2+ , PTH secretion and renal calcium and magnesium reabsorption are suppressed and the disease is characterized by inappropriately low serum PTH and increased calcium and magnesium excretion. Elevated urinary calcium may lead to nephrolithiasis despite increased magnesium excretion. The hypomagnesemia is usually asymptomatic, but significant deficiencies have been reported [59] . Some of this variability is due to the heterogeneity of the activating mutations and a corresponding variability in set-point displacement for serum Ca+ and Mg+ concentrations.

Familial Hypocalciuric Hypercalcemia and Neonatal Severe Hyperparathyroidism.

Familial hypocalciuric hypercalcemia [60] [61] [62] [63] and neonatal severe hyperparathyroidism result from inactivating heterozygous and homozygous mutations, respectively [57] [64] [65] . Renal excretion of calcium and magnesium is reduced, which leads to hypercalcemia and sometimes hypermagnesemia [60] [61] [62] [63] . Defective extracellular Casr likely leads to inappropriate absorption of calcium and magnesium in the TAL [10] and magnesium transport in the distal tubule [17] . A knockout mouse model displays all of the characteristics of familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism, providing experimental evidence to support this idea [66] .

Although the human mutations indicate that magnesium regulation is not the primary function of the Casr gene, the possibility exists that specific defects of the sensing mechanism may affect renal magnesium balance. Bapty et al. [17] observed that the sensitivity of divalent sensing may be greater for extracellular Mg2+ than Ca2+ in immortalized mouse DCT cells. The effects of extracellular Ca2+ and Mg2+ were not additive. Whether this is due to selective receptors or ion-specific effects on the same receptor is not clear. The ligand-binding and signal transduction properties of the Ca2+ /Mg2+ -sensing receptor protein are still to be elucidated.

Mehrotra et al. [67] described a 44-yr-old male with marked hypomagnesiuric hypermagnesemia and hypocalciuria but normocalcemia that they speculated was due to abnormal Ca2+ /Mg2+ sensing. However, the presence of progressive renal failure, the concomitant hypokalemic metabolic alkalosis, and the absence of confirmatory molecular data make an inherited defect of the Casr in this patient less likely.

Hypomagnesemia Associated With Abnormal NaCl Transport

Gitelman syndrome and Bartter syndrome are two autosomal-recessive disorders of renal electrolyte transport that have been associated with hypokalemia as a result of renal potassium loss, chloride-resistant metabolic alkalosis, and elevated plasma renin and aldosterone levels but normal BP (Table 2) [68] [69] . In Gitelman syndrome, hypomagnesemia is a distinctive feature [68] , whereas there is doubt as to whether disordered magnesium metabolism is ever significantly abnormal in patients with true Bartter syndrome [70] [71] .

Gitelman Syndrome.

Patients with Gitelman syndrome often present in late childhood with a hypokalemic metabolic alkalosis and low serum magnesium, which may be asymptomatic or may be severe enough to cause hypomagnesemic tetany [72] [73] . Patients are not polyuric or polydipsic but have hypocalciuria and usually show renal magnesium wasting [74] . The absence of nephrocalcinosis, which may be best defined by renal ultrasound, therefore is an important diagnostic feature.

Skeletal problems are occasionally observed in children with Gitelman syndrome. Some children without severe renal defects will present with growth retardation as a result of rickets. The other causes of renal rickets can be rapidly excluded by characterizing the abnormality of renal magnesium handling. Bettinelli et al. [75] described a variant form of Gitelman syndrome with intermittent electrolyte abnormalities but severe growth failure. The two affected children were unrelated but had growth hormone deficiency and partial vasopressin insufficiency associated with an empty sella on intracranial imaging. Pituitary screening may be warranted in patients in whom growth failure is a prominent feature. Gitelman syndrome is also characterized by chondrocalcinosis [76] [77] and rarely rhabdomyolysis that is secondary to severe hypokalemia [78] , but the long-term outlook for these patients is good [79] . Treatment with oral magnesium corrects the magnesium deficit but not the metabolic alkalosis [80] , and careful management of the potassium wasting is important. The relationship of these skeletal abnormalities to magnesium wasting and hypomagnesemia is unclear.

Patients with Gitelman syndrome fail to respond to chlorothiazide, leading to the prediction that the renal defect is in the DCT [81] . Simon et al. [82] showed that Gitelman syndrome families are genetically linked to a locus at 16q13 and identified causative mutations in the chlorothiazide-sensitive NaCl cotransporter expressed in the DCT (NCCT/SLC12A3). As chlorothiazide enhances calcium reabsorption in this nephron segment, the hypocalciuria of Gitelman syndrome is readily explained [71] . The reasons for renal magnesium wasting are unknown [8] . We have shown that chlorothiazide stimulates Mg2+ uptake in mouse DCT cells by mechanisms similar to those that increase Ca2+ entry [8] . One would predict, therefore, that hypomagnesiuria should be the prevailing phenotype, rather than increased renal magnesium excretion. Reilly and Ellison [83] recently postulated another way to explain magnesium wasting of patients with Gitelman syndrome. They suggested that the absence of claudin 16 expression may somehow allow magnesium secretion via the paracellular pathway, thus leading to increased urinary excretion. The notion is that Gitelman syndrome converts some DCT cells that are predominantly electroneutral cells to cells that reabsorb Na+ in an electrogenic manner. As discussed by these authors, the cells are also responsive to the actions of aldosterone. Accordingly, the combination of the dominance of electrogenic ion transport pathways, the stimulation by aldosterone, and the increased Na+ concentration all favor electrogenic Na+ reabsorption that greatly increases the magnitude of the transepithelial voltage [83] . The luminal negative voltage drives magnesium secretion. We do not favor this explanation as our earlier micropuncture studies failed to detect any Mg2+ secretion in microperfused distal tubules [8] . By deleting the gene coding for the NaCl cotransporter, Schulteis and colleagues [84] developed a mouse model of Gitelman syndrome. These mice show all of the cardinal features of Gitelman syndrome, including renal magnesium wasting, so this knockout model may be useful in delineating the molecular physiology of this condition.

Bartter Syndrome.

Patients with infantile Bartter syndrome characteristically present in infancy with a urinary concentrating defect, polyhydramnios, failure to thrive, and fasting hypercalciuria leading to medullary nephrocalcinosis [85] . Those with classic Bartter syndrome present in childhood with features of water and salt depletion, including polydipsia, polyuria, and episodes of dehydration. Clinical features may include growth retardation, developmental delay, nephrocalcinosis, and hydronephrosis as a result of impaired water clearance [25] [71] . Patients fail to respond normally to furosemide, suggesting to investigators that this disease was due to defective loop function. Using family linkage studies, Simon et al. [86] [87] [88] delineated three genetic defects that form the basis for distinguishing three distinct physiologic phenotypes in these patients. Type I Bartter syndrome is due to defective Na-K-Cl cotransport (NKCC2 gene), characterized by severe hypokalemia in addition to the above [86] . Type II Bartter syndrome is associated with mutations in a potassium channel (ROMK gene, 30 pS K+ channel) activity [87] . As this K+ channel is also present in the cortical collecting duct and is involved in potassium secretion in this segment, hypokalemia is less severe in this form of the disease. Type III Bartter syndrome is based on a mutation in the basolateral membrane chloride channel (ClCNKB) [88] . Like type I patients, type III patients have severe hypokalemia, but unlike Type I and Type II phenotypes, nephrocalcinosis is not observed.

Additional phenotypes have been reported, and genetic evidence for further heterogeneity has been presented [70] [88] [89] [90] [91] [92] . A form of infantile Bartter’s syndrome that is consistently associated with sensorineural deafness has been described in some Bedouin families [89] . Although there is no evidence that the renal defect differs from that observed in isolated Bartter’s syndrome, genetic linkage to chromosome 1p31 tends to exclude any of the three transport defects identified to date [90] , despite the proximity to the ClCNKB gene (1p36) of type III Bartter syndrome [88] . Speculation by Brennan et al. [90] that another Na-K-Cl transporter is involved is supported by the recent identification of a specific sensorineural deafness syndrome in knockout mice that lack a second, more widely expressed Na-K-Cl cotransporter gene [91] .

It has been suggested that up to 30% of patients with Bartter syndrome may have hypomagnesemia as a result of renal magnesium wasting. However, it is clear that some of these cases represent a form of Gitelman syndrome, and others may be another variant of hypokalemic metabolic alkalosis. In addition, hypomagnesemia does not reliably segregate to any of the three types of Bartter syndrome defined by molecular studies, suggesting that other circumstances may affect renal magnesium absorption. Supporting this notion is evidence that magnesium balance is normal in a Na-K-Cl cotransport knockout mouse mimicking type I Bartter syndrome [93] . Chronic use of furosemide is sometimes associated with hypomagnesemia as a result of excessive urinary magnesium excretion, but it is not universal [8] . Thus, it is not apparent why most individuals with Na-K-Cl cotransport defects should be comparatively free of renal magnesium wasting. It may be that the loop and distal tubule adapt to conserve magnesium in this disorder [1] [8] .

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