Hypomagnesemia: Practice Essentials, Pathophysiology, Etiology (original) (raw)

Overview

Practice Essentials

Hypomagnesemia—serum magnesium levels below the normal range of 1.7 to 2.3 mg/dL (1.4 to 2.1 mEq/L, 0.7 to 1.05 mmol/L)—is common in clinical practice. It results mainly from gastrointestinal or renal loss (eg, diarrhea, diuretic use) and to a lesser extent from decreased intake or magnesium redistribution between the extracellular and intracellular spaces. It can be acquired or hereditary. (See Etiology.)

Despite the well-recognized importance of magnesium, it is not included in routine laboratory assessments and must be specifically ordered based on clinical suspicion. [1, 2] Consequently, magnesium has sometimes been called the "forgotten cation." [3, 4]

Symptomatic hypomagnesemia commonly presents as involvement of the cardiovascular system and the central and peripheral nervous systems. However, magnesium deficiency can result in disturbances in nearly every organ system and can cause potentially fatal complications (eg, ventricular arrhythmia, coronary artery vasospasm, sudden death). In the setting of symptomatic hypomagnesemia, the serum magnesium level is usually very low and it is often accompanied by refractory hypokalemia and hypocalcemia [5] See Presentation.

For the most part, the signs and symptoms of hypomagnesemia are reversible with magnesium replacement. Therapy can be given orally for patients with mild symptoms or intravenously for patients with severe symptoms or those unable to tolerate oral administration. Sources of magnesium loss may also need to be addressed. See Treatment and Medication.

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Pathophysiology

Magnesium is the second-most abundant intracellular cation and, overall, the fourth-most abundant cation. [6] It plays a fundamental role in many functions of the cell, including energy transfer, storage, and use; protein, carbohydrate, and fat metabolism; maintenance of normal cell membrane function; and the regulation of parathyroid hormone (PTH) secretion. Systemically, magnesium lowers blood pressure and alters peripheral vascular resistance.

Almost all enzymatic processes using phosphorus as an energy source require magnesium as a cofactor or for activation. Magnesium is involved in nearly every aspect of biochemical metabolism (eg, DNA and protein synthesis, glycolysis, oxidative phosphorylation). Almost all enzymes involved in phosphorus reactions (eg, adenosine triphosphatase [ATPase]) require magnesium for activation.

More than 600 enzymes need magnesium as a cofactor and around 200 need it for activation. Magnesium serves as a molecular stabilizer of RNA, DNA, and ribosomes. Because magnesium is bound to adenosine triphosphate (ATP) inside the cell, shifts in intracellular magnesium concentration may help to regulate cellular bioenergetics, such as mitochondrial respiration. [7]

Extracellularly, magnesium ions block neurosynaptic transmission by interfering with the release of acetylcholine. Magnesium ions also may interfere with the release of catecholamines from the adrenal medulla. Magnesium has been proposed as an endogenous endocrine modulator of the catecholamine component of the physiologic stress response.

Magnesium homeostasis

The total body magnesium content of an average adult is 24 g (1000 mmol, 2000 mEq). Approximately 60% of the body's magnesium is present in bone, 20% is in muscle, and another 20% is in soft tissue and the liver. Approximately 99% of total body magnesium is intracellular or bone-deposited, with only 1% present in the extracellular space. Extracellularily, magnesium is found in one of 3 forms: ionized and physiologically active (60% of plasma magnesium), complexed to filterable ions (eg, oxalate, phosphate, citrate), or protein bound (3-30%). Both the ionized and the complexed forms are available for glomerular filtration.

Normal plasma magnesium concentration is 1.7-2.3 mg/dL (0.7-1.05 mmol, 1.4-2.1 mEq/L). [7] .

The main controlling factors in magnesium homeostasis appear to be gastrointestinal absorption and renal excretion. The average American diet contains approximately 360 mg (ie, 15 mmol or 30 mEq) of magnesium; healthy individuals need to ingest 0.15-0.2 mmol/kg/d to stay in balance. Magnesium is ubiquitous in nature and is especially plentiful in green vegetables, cereals, grains, nuts, legumes, and chocolate. Vegetables, fruits, meats, and fish have intermediate values. Food processing and cooking may deplete magnesium content, thus accounting for the apparently high percentage of the population whose magnesium intake is less than the daily allowance.

The plasma magnesium concentration is kept within narrow limits. Extracellular magnesium is in equilibrium with that in the bones and soft tissues (eg, the kidneys and intestines). In contrast with other ions, magnesium is treated differently in two major respects: first, bone, the principal reservoir of magnesium, does not readily exchange magnesium with circulating magnesium in the extracellular fluid space; and second, only limited hormonal modulation of urinary magnesium excretion occurs. [8, 9, 10] This inability to mobilize magnesium stores means that in states of negative magnesium balance, initial losses come from the extracellular space; equilibrium with bone stores does not begin for several weeks.

Magnesium absorption

Magnesium is absorbed principally in the distal ilieum and colon, through a saturable transport system and via passive diffusion through bulk flow of water. Absorption of magnesium depends on the amount ingested. When the dietary content of magnesium is typical, approximately 30-40% is absorbed. Under conditions of low magnesium intake (ie, 1 mmol/d), approximately 80% is absorbed, while only 25% is absorbed when the intake is high (25 mmol/d).

Active transcellular transport takes place through transient receptor potential channel melstatin member 6 and 7 (TRPM 6 and TRPM7), with cell exit at the basolateral side through sodium magnesium exchanger cyclin M4. Transcellular absorption plays an important role when dietary magnesium intake is low. [11, 12] Mutations in TRPM 6 have been identified as a cause of familial hypomagnesemia with secondary hypocalcemia. [13, 14]

The exact mechanism by which alterations in fractional magnesium absorption occur has yet to be determined. Presumably, only ionized magnesium is absorbed. Increased luminal phosphate or fat may precipitate magnesium and decrease its absorption.

In the gut, calcium and magnesium intakes influence each other's absorption: a high calcium intake may decrease magnesium absorption, and a low magnesium intake may increase calcium absorption. Parathyroid hormone (PTH) appears to increase magnesium absorption. Glucocorticoids, which decrease the absorption of calcium, appear to increase the transport of Mg+2. Vitamin D may increase magnesium absorption, but its role is controversial.

Renal handling of magnesium

Unlike most ions, the majority of magnesium is not reabsorbed in the proximal convoluted tubule (PCT). Micropuncture studies, in which small pipettes are placed into different nephron segments, indicate that the thick ascending limb (TAL) of the loop of Henle is the major site of reabsorption (60-70%); see the image below. The PCT accounts for only 15-25% of absorbed magnesium, and the distal convoluted tubule (DCT), for another 5-10%. [15] No significant reabsorption of magnesium occurs in the collecting duct. [16]

in the PCT, magnesium absorption takes place through a passive paracellular process that is unregulated and remains unsaturable and in linear propotion with luminal magnesium concentration. Inherited disorders of magnesium transport, although rare, may involve any of an array of underlying biochemical abnormalities. The identification of additional genetic disorders causing hypomagnesemia and the development of transgenic mice models has notably improved the understanding of the molecular basis of magnesium handling by the kidneys. [17]

In the TAL, magnesium is passively reabsorbed with calcium through paracellular tight junctions; the driving force behind this reabsorption is a lumen-positive electrochemical gradient, which results from the reabsorption of sodium chloride through the Na+- K+-Cl− cotransporter 2 (NKCC2) channel. This channel recycles potassium back to the lumen through the renal outer medullary potassium (ROMK) channel, adding a positive charge.

Claudins are the major components of tight-junction strands in the TAL, where the reabsorption of magnesium and calcium occur. [18, 19] Magnesium reabsorption in the TAL is highly regulated by the serum level of magnesium and consequent delivary of magnesium to the segment. However, understanding of the exact mechanisms of this regulatory pathway remains limited.

In humans, mutations in the genes that code for claudin-16 (previously known as paracellin-1) and claudin-19 cause a hereditary disease, familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), that is characterized by renal magnesium and calcium wasting, polyuria, recurrent urinary tract infections, bilateral nephrocalcinosis, and progressive kidney failure. [20, 21, 22] Mutations in claudin-19 are also associated with severe ocular involvement that may include myopia, nystagmus, or coloboma. [23]

Claudin-16 interacts with claudin-19 only, while claudin-19 interacts with other claudins in the TAL. Single-cell RNA-sequencing experiments has shown differential abundance of different claudins over TAL. Claudin-16 is more expressed in the cortical TAL, while claudin-10b (which mediates paracellular sodium reabsorption) is highly expressed in medullary TAL; this confirms that some distinct areas of the TAL apprear to specialize in paracellular magnesium or sodium reabsorption. [24, 25]

Claudin-14 is also highly expressed in the TAL and its expression is directly proportional to dietary magnesium intake. Claudin-14 may directly block claudin-16 and claudin-19, thus modulating paracellular magnesium absorption. [26]

The calcium-sensing receptor (CaSR) is another regulator of magnesium reabsorption. It is located at the basolateral side of the TAL cells. About 50% of patients diagnosed with autosomal dominant hypocalcemia with hypercalcuria (ADHH) due to gain-of-function mutations of CaSR exhibit hypomagnesemia. Stimulation of CaSR reduces NKCC2 and ROMK channel activities; this attenuates positive electrical potential in the lumen, which is crucial for paracellular magnesium reabsorption.

Moreover, CaSR can upregulate claudin-14 through microRNAs (mIR-9 and mIR-374) and inhibit claudin-16 and claudin-19, thus decreasing paracellular magnesium reabsorption. [27] Several gain-of-function mutation of CaSR can result in Bartter syndrome type V, which has hypomagnesemia as one of its features.

Recently, RagD, a small guanosine triphosphatase, was identified as a regulator of magnesium reabsorption in TAL and DCT cells. RagD stimulates the mechanistic target of rapamycin complex 1 (mTOR1) pathway. Mutations in RRAGD, the gene that encodes for RagD, causes autosomal dominant kidney hypomagnesemia. [28]

In the DCT, magnesium is reabsorbed via an active transcellular process that is thought to involve TRPM6, a member of the transient receptor potential (TRP) family of cation channels. [29, 30] Mutations in TRPM6 have been identified as the underlying defect in patients with hypomagnesemia with secondary hypocalcemia (HSH), [15, 13, 31, 14] an autosomal-recessive disorder that manifests in early infancy with generalized convulsions refractory to anticonvulsant treatment or with other signs of increased neuromuscular excitability, such as muscle spasms or tetany. Laboratory evaluation reveals extremely low serum magnesium and serum calcium levels.

Mutations of the epithelial growth factor receptor (EGFR) gene have been associated with reduced expression of TRPM6. [32, 9] An inactivating mutation of EGFR causes the genetic disorder isolated recessive hypomagnesemia (IRH), in which EGFR inactivation promotes TRPM-6 downregulation and decreases magnesium reabsorption in the DCT. [33]

In addition, cancer medications that are EGFR inhibitors (eg, cetuximab, panitumumab, zalutumumab) are associated with hypomagnesemia. [34] A meta-analysis of 25 randomized controlled trials that included 16,400 cancer patients receiving EGFR inhibitors reported a 34% rate of hypomagnesemia. [35] Hypocalcemia and hypokalemia were additional adverse effects, secondary to hypoglycemia. [36] Rates of hypomagnesemia and hypokalemia were highest with panitumumab, likely due to its longer half-life and highest affinity to the receptor, and lowest with zalutumumab, at 4%. [35, 37]

A low-magnesium diet increases uromodulin, the most abundant urinary protein. Uromodulin prevents endocytosis of TRPM-6, facilitating magnesium reabsorption in the DCT. Uromodulin also increases the expression of NKCC2 in the TAL, promoting paracellular passive reabsorption of magnesium in this segment. [38]

A guanosine triphosphatase (GTP)–binding protein encoded by ARL15 is expressed in the TAL and DCT and has been shown to regulate TRPM6-mediated currents. A variant ARL15 has been associated with renal magnesium wasting. [39]

Another channel that affects magnesium reabsorption indirectly in the DCT is the voltage-gated potassium channel subtype 1.1 (Kv1.1), which helps maintain the apical membrane potential and thus promotes magnesium passage through TRPM6/7. Kv1.1 is encoded by the KCNA1 gene and mutations in this gene result in isolated dominant hypomagnesemia (IDH). [40]

The mechanism of basolateral transport into the interstitium is unknown. Magnesium has to be extruded against an unfavorable electrochemical gradient. Most physiologic studies favor a sodium-dependent exchange mechanism driven by low intracellular sodium concentrations; these concentrations are generated by Na+/K+ - ATPase, also known as the sodium-potassium pump.

A mutation in the FXYD2 gene, which encodes the gamma subunit of Na+/K+ -ATPase, also causes IDH. These patients always have hypocalciuria and have variable (but usually mild) hypomagnesemic symptoms. [41, 42] The entry of K+ is reduced and the cell depolarizes to some extent, leading to closing of the TRPM6 channel and magnesium wasting.

Similarly, mutation in the Na-K ATPase alpha-1 subunit (ATPA1A) also causes hypomagnesemia. [43] Two channels located at the basolateral side that are important for maintaining the action of Na-K ATPase by recycling potassium are the inwardly-rectifying potassium channels Kir4.1 and Kir5.1, encoded by KCNJ10 and KCNJ16, respectively. A recessive mutation in KCNJ10 results in a rare condition known as EAST (Epilepsy, Ataxia, Sensorineural deafness, salt-losing Tubulopathy) or SeSAME (Seizures, Sensorineural deafness, Ataxia, Mental retardation, and Electrolyte imbalance) syndrome. [44] Another mutation of KCNJ16 has been associated with a similar phenotype, but without seizures or ataxia. [45]

More recently, multiple reports have highlighted the importance of mitochondrial function in magnesium handling. For example, pathogenic variants in mitochondrial DNA have been linked to a hereditary disorder similar to Gitelman syndrome (a salt-losing tubulopathy characterized by hypokalemic alkalosis and hypomagnesemia). The mechanism of this effect has yet to be fully elucidated. [46, 47]

A variety of factors influence the renal handling of magnesium. [48] For example, expansion of the extracellular fluid volume increases the excretion of calcium, sodium, and magnesium. Magnesium reabsorption in the loop of Henle is reduced, probably due to increased delivery of sodium and water to the TAL and a decrease in the potential difference that is the driving force for magnesium reabsorption.

Changes in the glomerular filtration rate (GFR) also influence tubular magnesium reabsorption. In chronic kidney disease, when the GFR and thus the filtered load of magnesium are reduced, fractional reabsorption is also reduced, such that the plasma magnesium value remains normal until the patient reaches end-stage renal disease (ESRD).

Phosphate depletion can also increase urinary magnesium excretion, through a mechanism that is not clear.

Chronic metabolic acidosis results in renal magnesium wasting: it decreases renal TRPM6 expression in the DCT, increases magnesium excretion, and thus decreases the serum magnesium concentration. In contrast, chronic metabolic alkalosis has the exact opposite effects. [49]

No single hormone has been implicated in the control of renal magnesium reabsorption. In experimental studies, a number of hormones have been shown to alter magnesium transport in the TAL. These include PTH, calcitonin, glucagon, arginine vasopressin (AVP), and beta-adrenergic agonists, all of which are coupled to adenylate cyclase in the TAL. Postulated mechanisms include an increase in luminal positive voltage (via activation of basolateral membrane chloride conductance and NKCC2) and an increase in paracellular permeability (possibly by the phosphorylation of paracellular pathway proteins). Whether these effects have an important role in normal magnesium hemostasis remains unknown.

Hypokalemia is common in patients with hypomagnesemia, occurring in 40-60% of cases. [1] This is partly due to underlying conditions that cause magnesium and potassium losses, including diuretic therapy and diarrhea.

Hypomagnesemia can induce hypokalemia by multiple mechanisms. Some involve the essential role of magnesium in normal function of Na-K ATPase, sodium-potassium cotransport, and other transport processes. [50]

The main mechanism relates to the intrinsic biophysical properties of the renal outer medullary potassium (ROMK) channel mediating K+ secretion in the TAL and the distal nephron. This channel is the pathway to potasium back-leak through the apical side into the urine. A high intracellular magnesium level is needed to inhibit the ROMK channel. With hypomagnesemia, the decrease in magnesium levels releases the inhibitory effect and causes potassium loss, resulting in hypokalemia. For that reason, correction of hypomagnesemia is crucial before starting potassium replacement and potassium-sparing diuretics as treatment for hypokalemia. [51]

Hypocalcemia is classically present with severe hypomagnesemia (< 1.2 mg/dL). The mechanism is multifactorial. Parathyroid gland function is abnormal; principally, release of PTH is decreased due to impaired magnesium-dependent adenyl cyclase generation of cyclic adenosine monophosphate (cAMP). [52] Altered activation of CaSR also has been suggested as a cause of low PTH. [53] Other mechanisms include increased PTH metabolism, end-organ PTH resistance, and decreased vitamin D levels.

Arrhythmia

The cardiovascular effects of magnesium deficiency include effects on electrical activity, myocardial contractility, potentiation of digitalis effects, and vascular tone. [54] Epidemiologic studies also show an association between magnesium deficiency and coronary artery disease (CAD).

Hypomagnesemia can cause cardiac arrhythmia. [55, 56, 57] Electrocardiographic changes include prolongation of conduction and slight ST depression.

Patients with magnesium deficiency are particularly susceptible to digoxin-related arrhythmia. Intracellular magnesium deficiency and digoxin excess act together to impair Na+/K+ -ATPase. The resulting decrease in intracellular potassium disturbs the resting membrane potential and repolarization phase of the myocardial cells, enhancing the inhibitory effect of digoxin. Intravenous magnesium supplementation may be a helpful adjunct when attempting rate control for atrial fibrillation with digoxin. [58]

Non–digitalis-associated arrhythmias are myriad. The clinical disturbance of greatest importance is the association of mild hypomagnesemia with ventricular arrhythmia in patients with cardiac disease. At-risk patients include those with acute myocardial ischemia, chronic heart failure, or recent cardiopulmonary bypass, as well as acutely ill patients in the intensive care unit. [55]

The ionic basis of the effect of magnesium depletion on cardiac arrhythmia may be related to impairment of the membrane sodium-potassium pump and the increased outward movement of potassium through the potassium channels in cardiac cells, leading to shortening of the action potential and increasing susceptibility to cardiac arrhythmia. [59] Torsade de pointes, a repetitive, polymorphous ventricular tachycardia with prolongation of the QT interval, has been reported in conjunction with hypomagnesemia, and the American Heart Association recommends considering adding magnesium sulfate to the regimen used to manage torsade de pointes or refractory ventricular fibrillation. [60]

Meta-analysis of 7 randomized trials showed that intravenous magnesium replacement decreased the incidence of atrial fibrillation following coronary artery bypass grafting (CABG). [61] In a more recent randomized, controlled trial, preoperative oral magnesium supplementation for 3 days significantly decreased the incidence of postoperative atrial fibrillation in CABG patients (relative risk = 0.45, 95% confidence interval 0.23–0.91). [62]

Hypertension

Magnesium has been suggested to play a role in blood pressure regulation, its therapeutic efficacy in the hypertensive syndromes of pregnancy having been demonstrated in the 19th century. Hypertension appears to be uniformly characterized by a decrease in intracellular free magnesium that, due to increased vascular tone and reactivity, causes an increase in total peripheral resistance.

At the cellular level, increased intracellular calcium content is believed to account for this increased tone and reactivity. This increased cytosolic calcium concentration may be secondary to decreased activation of calcium channels, which may enhance calcium current into cells, decrease calcium efflux from cells, increase cellular permeability to calcium, or decrease sarcoplasmic reticulum reuptake of intracellularly released calcium.

Whatever the cause, intracellular accumulation leads to activation of actin-myosin contractile proteins, which increases vascular tone and total peripheral resistance. In contrast to experimental cellular physiology data supporting a role for magnesium deficiency in hypertension, results from clinical epidemiologic studies have failed to confirm a relationship, and results from clinical trials examining the hypotensive effects of magnesium supplementation have been conflicting, possibly due to the high heterogeniety of studies.

Nevertheless, a meta-analysis of a subgroup of patients with uncontrolled blood pressure on treatment showed beneficial effects of oral magnesium on blood pressure control. [63] Noticeably, in the DASH study (Dietary Approaches to Stop Hypertension), a diet rich in fruits and vegetables (rich in potassium and magnesium) resulted in lowering of blood pressure. [64] Larger, carefully performed, randomized clinical trials are needed to confirm these findings; the design of these trials needs to take into consideration that the benefit of magnesium supplementation may be limited to specific groups of patients.

Coronary artery disease

In epidemiologic studies, patients with CAD have a higher incidence of magnesium deficiency than do control subjects. [65, 66] Mounting evidence suggests that magnesium deficiency may play a role in the pathogenesis, initiation, morbidity, and mortality associated with myocardial infarction.

In experimental animals, arterial atherogenesis varied inversely with dietary magnesium intake. In humans, the level of serum magnesium is inversely related to the serum cholesterol concentration. Therefore, magnesium deficiency is associated with hypertension and hypercholesterolemia, which are well-recognized risk factors for atherogenesis and CAD.

Magnesium deficiency is also known to be accompanied by thrombotic tendencies, increased platelet aggregatability, and increased coronary artery responsiveness to contractile stimuli. These factors are important in the initiation of acute myocardial infarction. Also, hypomagnesemia has been associated with atherosclerosis [67] and other risk factors of CAD, including metabolic syndrome, hypertension and diabetes mellitus.

A study of 2640 adults older found that a higher kidney reabsorption-related magnesium depletion score (MDS) and older age were associated with a higher incidence of calcification in the abdominal aorta. The study authors propose that the MDS may help identify patients with magnesium deficiency who would benefit from magnesium supplementation. [68]

Research is conflicting regarding the benefits of intravenous administration of magnesium in the setting of acute myocardial infarction. A 16% reduction in all-cause mortality was noted in a study of 2316 patients. [69] Disappointingly, 2 other large studies failed to confirm this benefit. [70, 71]

The incidence of cardiac arrhythmia also correlates with the degree of magnesium deficiency in patients with CAD. Preliminary data suggest that magnesium supplementation may reduce the frequency of potentially fatal ventricular arrhythmia, although this finding has not been conclusively proven.

Hypomagnesemia can also develop during cardiopulmonary bypass and predispose the patient to arrhythmia. [72] Intravenous magnesium given after the termination of cardiopulmonary bypass has resulted in significantly lower incidence rates of supraventricular and ventricular dysrhythmia, in relatively small trials of adult [73, 74] and pediatric [75] patients. Considering the above data, carefully assessing magnesium status in patients with CAD and supplementing patients deficient in magnesium seems prudent. The routine use of magnesium supplements in myocardial infarction remains controversial in the era of thrombolytics and percutaneous coronary interventions.

Neuromuscular manifestations

The earliest manifestations of magnesium deficiency are usually neuromuscular and neuropsychiatric disturbances, the most common being hyperexcitability. Neuromuscular irritability, including tremor, fasciculations, tetany, Chvostek and Trousseau signs, and convulsions, has been noted when hypomagnesemia has been induced in volunteers. Other manifestations include the following:

Neuronal magnesium is crucial for controlling excitability of N-methyl-D-aspartate (NMDA) receptors. NMDA is involved in learning, developmental plasticity, and memory. [76] This process is further regulated and amplified by inhibitory gamma-aminobutyric acid (GABA) signaling, which is also regulated by magnesium. [77]

Magnesium is required for stabilization of the axon. The threshold of axon stimulation is decreased and nerve conduction velocity is increased when serum magnesium is reduced, leading to an increase in the excitability of muscles and nerves. The cellular basis for these changes is due to increased intracellular calcium content, by mechanisms similar to those described above for hypertension.

There is some evidence that hypomagnesemia may contribute to the pathophysiology of the following neurologic disorders:

Osteoporosis

Magnesium deficiency has been implicated in osteoporosis. [85] The magnesium content in trabecular bone is significantly reduced in patients with osteoporosis, and magnesium intake in people with osteoporosis reportedly is lower than in control subjects. [86] (Magnesium intake frequently is lower than the recommended dietary intake in many groups, especially elderly persons.) [87]

Postmenopausal women are encouraged to consume at least 1000 mg of elemental calcium per day, which leads to altered dietary calcium-to-magnesium ratios. This calcium supplementation may reduce the efficacy of magnesium absorption and further aggravate the consequences of diminished estrogen and the greater demineralizing effects of PTH. The H+-K+-ATPase pump in the cells of the periosteum is magnesium dependent, which may lead to decreased pH in the bone extracellular fluid and increased demineralization. In addition, because the formation of calcitriol involves a magnesium-dependent hydroxylase enzyme, calcitriol concentrations are reduced in magnesium deficiency, possibly affecting calcium reabsorption.

Magnesium supplementation may be beneficial in osteoporosis and may increase bone density, arrest vertebral deformity, and decrease osteoporotic pain. In the large joints, chondrocalcinosis is associated with long-term magnesium depletion. [88]

Nephrolithiasis

Urinary magnesium is an inhibitor of urinary crystal formation in vivo, and some studies have shown a lower urinary excretion of magnesium in patients with stones. Magnesium deficiency due to etiologies other than renal wasting is associated with hypomagnesuria and, theoretically, could play a role in predisposition to urinary calculus formation.

Diabetes

Patients with diabetes mellitus are often magnesium deficient, expressed by hypomagnesemia. Magnesium deficiency decreases insulin sensitivity and secretion. [89, 90] Moreover, magnesium deficiency is inherently related to the pathogenesis and development not only of diabetic microangiopathy such as in retinopathy [91] but also of lifestyle-related diseases, such as hypertension and hyperlipidemia. [92, 93] It is also associated with worse disease outcome and increased mortality in diabetic patients. [94] Magnesium deficiency may be a link with both inflammation and vascular stiffness in certain populations. [95]

Generally, modern people tend to live in a state of chronic dietary magnesium deficiency. [96] There is a possibility that one of the major factors contributing to the drastic increase of type 2 diabetes mellitus is the drastically decreased intake of grains, such as barley or cereals, rich in magnesium. [97] A meta-analysis of randomized controlled trials showed that oral magnesium supplementation has a favorable effect on diabetes control. [98] Hypomagnesemia is also associated with higher incidence of new-onset diabetes after kidney or liver transplantation. [99, 100]

This implies an association between the volume of dietary magnesium intake and the onset of type 2 diabetes. It is possible that in future, clinical trials will be performed to investigate the efficacy of magnesium supplementation therapy.

Preeclampsia

For decades, magnesium sulfate has been well established in the management of pre-eclampsia and eclampsia. [101] Proposed mechanisms of action are the vasodilator effect of magnesium and its ability to block NMDA receptors, preventing seizures and decreasing cerebral edema. [102] A Cochrane review confirmed that treatment with magnesium sulfate decreased progression to eclampsia by > 50% and decreased maternal mortality. [103] Risk prediction for pre-eclampsia can be improved by measuring ionized magnesium, rather than the total magnesium concentration in blood. [104]

Miscellaneous conditions

Magnesium status may have an influence on asthma, because magnesium deficiency is associated with increased contractility of smooth muscle cells. Magnesium supplementation in asthma remains controversial, [105] but it has been shown to reduce bronchial hyperreactivity to methacholine and other measures of allergy. [106]

The following conditions have also been linked to magnesium deficiency:

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Etiology

Hypomagnesemia can result from decreased intake, redistribution of magnesium from the extracellular to the intracellular space, or increased renal or gastrointestinal loss. Medications can cause hypomagnesemia through a variety of mechanisms. An additional element of variability is the difference between total versus ionized magnesium concentration, the latter being influenced by plasma protein concentration and the acid-base status. [104] In some cases, more than one cause may be present.

Decreased magnesium intake

North American and European epidemiologic studies show that 30-50% of the population consumes less than the recommended amounts of magnesium. [107, 108] Other ennviromental and agronomic factors decrease magnesium content in the soil and in the food chain. [109] Moreover, alcoholics and individuals on magnesium-deficient diets or on parenteral nutrition for prolonged periods can become hypomagnesemic without abnormal gastrointestinal or kidney function. The addition of 4-12 mmol of magnesium per day to total parenteral nutrition has been recommended to prevent hypomagnesemia.

The Recommended Dietary Allowance (RDA) for magnesium is age dependent, as follows [110] :

Redistribution of magnesium

The transfer of magnesium from the extracellular space to intracellular fluid or bone is a frequent cause of decreased serum magnesium levels. This depletion may occur as part of hungry bone syndrome, [111] in which magnesium is removed from the extracellular fluid space and deposited in bone following parathyroidectomy or total thyroidectomy or any similar states of massive mineralization of the bones. [112, 113]

Hypomagnesemia may also occur following insulin therapy for diabetic ketoacidosis and may be related to the anabolic effects of insulin, which drive magnesium, along with potassium and phosphorus, back into cells.

Hyperadrenergic states, such as alcohol withdrawal, may cause intracellular shifting of magnesium and may increase circulating levels of free fatty acids that combine with free plasma magnesium. The hypomagnesemia that sometimes is observed after surgery is attributed to the latter.

Hypomagnesemia is a manifestation of the refeeding syndrome, a condition in which previously malnourished patients are fed high carbohydrate loads, resulting in a rapid fall in phosphate, magnesium, and potassium, along with an expanding extracellular fluid space volume, leading to a variety of complications. [114]

Acute pancreatitis can also cause hypomagnesemia. The mechanism may represent saponification of magnesium in necrotic fat, similar to that of hypocalcemia. However, postoperative states [115] or critical illnesses in general are associated with low magnesium levels, [116] without pancreatitis necessarily being present.

Medications that can shift magnesium to intracellular compartment are epinephrine, terbutaline, salbutamol, theophyline, insulin, metformin, and alkali therapy. [2]

Gastrointestinal losses

Impaired gastrointestinal magnesium absorption is a common underlying basis for hypomagnesemia, especially when the small bowel is involved, due to disorders associated with malabsorption, chronic diarrhea, or steatorrhea, or as a result of bypass surgery on the small intestine. Because some magnesium absorption take place in the colon, patients with ileostomies can develop hypomagnesemia.

Medications that can cause hypomagnesemia due to gastrointestinal loss include the following:

PPIs, which are widely used to reduce gastric acid secretion, are clearly associated with hypomagnesemia. [118, 119, 120, 121, 122] The likely mechanism is impaired active absorption of magnesium in colon through TRPM6/TRPM7. [117] A meta-analysis of 16 observational studies including 131,000 patients showed that PPI exposure was associated with hypomagnesemia with a pooled adjusted odds ratio of 1.71 (95% CI, 1.33 to 2.19; P < 0.001). [123] Additional risk factors are concomitant diuretic use, higher PPI dose, long-term PPI use, chronic kidney disease (CKD), and older age. [123]

In 2011 the US Food and Drug Administration (FDA) issued a safety warning that prolonged use of PPIs (in most cases, for longer than 1 year) can lead to hypomagnesemia. The FDA advised healthcare professionals to consider obtaining serum magnesium levels prior to initiation of prescription PPI treatment in patients expected to be on these drugs for long periods of time, as well as in patients also taking other medications (eg, diuretics) that may cause hypomagnesemia and in those taking digoxin, as hypomagnesemia can increase the likelihood of serious adverse effects from digoxin. The FDA recommended considering periodic measurement of serum magnesium levels in those patients. [124]

A case-control study by Zipursky et al documented an association between use of PPIs and hospitalization with hypomagnesemia. Comparison of 366 patients hospitalized with hypomagnesemia and 1464 matched controls showed a 43% increased risk of hypomagnesemia in patients currently using PPIs (adjusted odds ratio [OR], 1.43; 95% confidence interval [CI] 1.06–1.93). The increased risk was significant among patients also taking diuretics, (adjusted OR, 1.73; 95% CI 1.11–2.70) but not among those not receiving diuretics (adjusted OR, 1.25; 95% CI 0.81–1.91). [125]

Bowel regimens that contain laxatives (including magnesium-containing ones) and bowel preparations can cause diarrhea and hypomagnesemia. [126] Colchicine may cause severe diarrhea, with secondary hypomagnesemia. Finally, polystyrene sulfonate and patiromer, which are used for treating hyperkalemia, may cause hypomagnesemia due to stool losses. A meta-analysis of clinical trials found that patiromer use was associated with hypomagnesemia in 7% of patients. [127]

Hypomagnesemia with secondary hypocalcemia (HSH) is a rare autosomal recessive disorder characterized by profound hypomagnesemia associated with hypocalcemia due to mutations in the genes coding for TRPM family channels. HSH type1 is due to mutation in TRPM6 [13] and HSH type 2 is due to mutation in TRPM7. [128] The pathophysiology involves impaired intestinal absorption of magnesium accompanied by renal magnesium wasting; see below.

Renal losses

Hypomagnesemia due to renal magnesium loss can result from inherited renal tubular defects [20, 22, 129, 130] or medications, [131] as well as the following:

Inherited tubular disorders that result in urinary magnesium wasting include the following:

Gitelman syndrome

Gitelman syndrome is an autosomal recessive condition caused by loss-of-function mutation of the SLC12A3 gene, which encodes the thiazide-sensitive NaCl cotransporter (NCCT). [136] This syndrome is characterized by hypokalemic metabolic alkalosis, hypomagnesemia, and hypocalciuria. [137]

Hypomagnesemia is found in most patients with Gitelman syndrome and is assumed to be secondary to the primary defect in the NCCT, but some data point to magnesium wasting as a primary abnormality. [138] Some studies have indicated that magnesium wasting in Gitelman syndrome may be due to down-regulation of TRPM6 in the DCT.

A Gitelman-like syndrome has been reported due to mutations in the mitochondrial MT-TF and MT-TI genes. The proposed principal mechanism is decreased ATP generation, causung Na+-Cl- cotransporter inhibition and subsequent decreased TRPM6 expression in the DCT. [47]

Bartter syndrome (type III):

The electrical gradient in the thick ascending limb of the loop of Henle (TAL) generated by the active transport of sodium, potassium, and chloride by Na-K-Cl cotransporter (NKCC2) aids in the reabsorption of magnesium. Five types of Bartter syndrome have been identified: type 1, due to mutation in the gene coding for NKCC2; type II due to ROMK channel gene mutation; type III, due to mutation in CICNKB (chloride channel Kb) gene; type IV, due to mutation in barttin, a component of the chloride channel; and type IV, due to mutations in CaSR. [7]

In most patients with other forms of Bartter syndrome, any tendency toward hypomagnesemia is corrected by increased reabsorption of magnesium in the DCT. In type III, however, basolateral chloride channels are also expressed in the DCT, which impedes increased reabsorption. [139]

Autosomal dominant hypomagnesemia (ADHMG)

This disorder may involve mutations in any of the following three genes:

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis

In FHHNC, an autosomal-recessive disorder, profound renal magnesium and calcium wasting occurs. The hypercalciuria often leads to nephrocalcinosis, resulting in progressive kidney failure. [22, 140]

FHHNC type 1 is caused by mutations in the gene CLDN16, which encodes for claudin-16, [21] a member of the claudin family of tight junction proteins that form the paracellular pathway for calcium and magnesium reabsorption in the TAL. FHHNC type 2 with ophthalmologic disease indicates potential claudin-19 mutation that presents with same renal symptoms as with FHHNC type 1 but with additional occular manifestations as macular coloboma, nystagmus and myopia. [141]

Autosomal dominant hypocalcemia with hypercalciuria (ADHH)

ADHH is another disorder of urinary magnesium wasting. [142] Affected individuals present with hypocalcemia, hypercalciuria, and polyuria, and about 50% of these patients have hypomagnesemia.

ADHH is produced by mutations of the CASR gene, which encodes for the calcium-sensing receptor (CaSR) that is located basolaterally in TAL and DCT and is involved in renal calcium and magnesium reabsorption. [143] Activating mutations shift the set point of the receptor, increasing its affinity of the mutant receptor for extracellular calcium and magnesium. This results in diminished PTH secretion and decreased reabsorption of divalent cations in the TAL and DCT, which leads to loss of urinary calcium and magnesium.

Isolated dominant hypomagnesemia (IDH) with hypocalciuria

IDH with hypocalciuria [144] is an autosomal dominant condition associated with few symptoms other than chondrocalcinosis. Patients always have hypocalciuria and variable (but usually mild) hypomagnesemic symptoms.

A mutation in the gene FXYD2, which codes for the gamma subunit of the basolateral Na+/K+-ATPase in the DCT, has been identified. This mutation in the gamma subunit is thought to produce a disturbed routing of the Na+/K+-ATPase complex to the basolateral membrane, leading to reduced expression of the Na+/K+-ATPase on the cell surface. [41, 42] Consequently, the entry of potassium is reduced and the cell depolarizes to some extent, leading to closing of the TRPM6 channel and magnesium wasting.

Autosomal dominant tubulointerstitial kidney disease (ADTKD)

Mutated hepatocyte nuclear factor 1B (HNF1B) is a transcription factor associated with MODY type 5. Approximately 50% of these patients have hypomagnesemia. it is believed that HNF1B drives FXYD2 transcription in the DCT. [145]

Isolated recessive hypomagnesemia (IRH) with normocalcemia

IRH with normocalcemia is an autosomal recessive disorder in which affected individuals present with symptoms of hypomagnesemia in infancy. Hypomagnesemia due to increased urinary magnesium excretion appears to be the only abnormal biochemical finding. IRH is distinguished from the autosomal dominant form by the lack of hypocalciuria. [33] It is caused by a mutation in the EGF gene, resulting in inadequate stimulation of renal epidermal growth factor receptor (EGFR), and thereby insufficient activation of the epithelial Mg2+ channel TRPM6, which results in magnesium wasting. [8]

Hypomagnesemia with secondary hypocalcemia (HSH)

HSH, also called primary intestinal hypomagnesemia, is an autosomal recessive disorder characterized by very low serum magnesium levels and low calcium levels. [146] Mutations in the gene coding for TRPM6 and TRPM7, members of the transient receptor potential (TRP) family of cation channels, have been identified as the underlying genetic defects for HSH type 1 and 2, respectively. [13, 31, 14, 128]

Patients usually present within the first 3 months of life with the neurologic signs of hypomagnesemic hypocalcemia, including seizures, tetany, and muscle spasms. As TRPM6/7 are expressed on gastrointestinal tract and renal cells, mutations have associated with decreased absorption of magnesium along with renal magnesium wasting. Untreated, HSH may result in permanent neurologic damage or may be fatal. Hypocalcemia is secondary to parathyroid failure and peripheral parathyroid hormone resistance as a result of sustained magnesium deficiency.

Usually, the hypocalcemia is resistant to calcium or vitamin D therapy. Normocalcemia and relief of clinical symptoms can be attained by administration of high oral doses of magnesium, up to 20 times the normal intake. As large oral amounts of magnesium may induce severe diarrhea and noncompliance in some patients, parenteral magnesium administration must sometimes be considered. Alternatively, continuous nocturnal nasogastric magnesium infusions have been proven to efficiently reduce gastrointestinal adverse effects.

Hypomagnesemia, seizures, and mental retardation syndrome (HSMR)

HSMR is due to loss-of-function mutation in the cyclin M2 gene (CNNM2), which encodes the basolateral magnesium transporter. The phenotype associated with this mutation includes hypomagnesemia, seizures, intellectual disability, and obesity. [147, 134] N-glycosylation of CNNM2 is catalyzed by ADP-ribosylation factor–like protein 15 (ARL 15), which is a negative regulator for magnesium transport. [148]

EAST/SeSAME syndrome

Two mutations responsible for EAST/SeSAME syndromes were identified in the KCNJ10 gene, which encodes for the inward rectifying potassium channel (Kir4.1). [44, 149] Kir4.1 is present in kidney cells, inner ear epithelial cells and glial cells. The Kir4.1 channel recycles recycles potassium to keep the Na+/K+-ATPase pump working. [150]

Hypokalemic tubulopathy and deafness (HKTD)

HKTD is due to mutation in KCNJ16. This gene encodes the Kir5.1 channel, which is part of the Kir4.1/Kir5.1 complex resposible for potassium recycling. HKTD has same phenotypic presentation as EAST/SeSAME except that it is without seizures or ataxia. [45]

Medications

Medications associated with renal magnesium loss include the following [2] :

Loop diuretics (eg, furosemide, bumetanide, ethacrynic acid), produce large increases in magnesium excretion through the inhibition of the electrical gradient necessary for magnesium reabsorption in the TAL. However, a Dutch study of 9820 patients found that loop diuretic use was associated with higher serum magnesium levels; in contrast, thiazide diuretic use (especially for longer than a year) was associated with lower serum magnesium levels and an increased risk of hypomagnesemia, except in patients taking a potassium-sparing diuretic in combination with a thiazide. [151]

Long-term thiazide diuretic therapy may enhance magnesium excretion by reducing renal expression levels of the epithelial magnesium channel TRPM6. [152] The decreased risk of hypomagnesemia with loop diuretics is mostly because of a compensatory increase in magnesium reabsorption in the DCT level by upregulation of TRPM6 or enhanced magnesium reabsorption in the PCT. [153]

Renal magnesium wasting from platinum-containing chemotherapy drugs occurs more commonly with cisplatin than with carboplatin or oxaliplatin. Up to 90% of patients receiving cisplatin will have hypomagnesemia, in the absence of intravenous magnesium prophylaxis. [154] Cisplatin-related hypomagnesemia worsens with higher doses. The primary mechanism of renal wasting is down-regulation of the TRPM6/EGF pathway, which decreases DCT magnesium transport. [155]

Cisplatin-induced hypomagnesemia may be persistent. In one study, 50% of patients remained hypomagnesemic 3 years after cisplatin exposure. [156] Cisplatin-induced Gitelman syndrome has been also reported. [157]

In addition to preventing hypomagnesemia during cisplatin therapy, magnesium replacement may reduce cisplatin nephrotoxicity. In a rat model, co-administration of magnesium with cisplatin reduced platinum accumulation and toxicity by regulating the expression of renal transporters. [158]

EGFR inhibitors (eg, cetuximab, panitumumab and zalutumumab) are associated with hypomagnesemia. [34] In a meta-analysis of 25 randomized controlled trials including 16,400 cancer patients receiving EGFR inhibitors, 34% of those patients developed hypomagnesemia. [35] Other electrolyte disorders from this class of drugs are hypocalcemia and hypokalemia were additional medications complications secondary to hypoglycemia. [36] Higher rates of hypomagnesemia and hypokalemia have been reported with panitumumab than with cetuximab or zalutumumab; the latter has the lowest rate of hypomagnesemia, 4%.The higher rates with panitumumub are mostly explained by its longer half-life and highest affinity to EGFR. [35, 37]

Factors that increase the risk of hypomagnesemia in patients receiving EGFR inhibitors are duration of therapy and concomitant use of PPIs and platinum-based agents. [159, 160]

Oral magnesium supplementation may be helpful in these cases but intravenous replacement is often needed with severe hypomagnesemia. In contrast to hypomagnesemia from platinum-based agents, hypomagnesemia from EGFR inhibitors usually resolves after treatment discontinuation. [34]

CNIs are thought to cause hypomagnesemia by suppressing TRPM6 expression and decreasing magnesium uptake in the DCT. [161] Hypomagnesemia from CNIs appears to be more common with tacrolimus than with cyclosporine. [162] CNI-induced hypomagnesemia is usually mild unless augmented by gastrointestinal loss from diuretic use.

CNIs are part of the immunosuppressive regimens used in kidney transplant recipients, and CNI-induced hypomagnesemia has been linked to the development of diabetes mellitus in these patients. [163] Other causal factors in theis setting include post-transplantation volume expansion, metabolic acidosis, insulin resistance, decreased GI absorption due to diarrhea, low dietary magnesium intake, and use of other drugs such as diuretics or proton pump inhibitors. [164]

Aminoglycosides are thought to induce the action of the CaSR on the TAL and DCT, producing magnesium wasting. [165] Amphotericin B–induced magnesium deficiency is associated with hypocalciuria, which suggests injury to the DCT. [166]

Other causes of renal magnesium wasting, and the likely mechanisms, include the following:

Finally, magnesium wasting can be seen as part of the tubular dysfunction that is observed with recovery from acute tubular necrosis or during a postobstructive diuresis.

Cystic fibrosis

Serum magnesium levels decrease with age in patients with cystic fibrosis (CF), and hypomagnesemia occurs in more than half of patients with advanced CF. In part, hypomagnesemia in these patients may result from use of aminoglycoside antibiotics, which can induce both acute and chronic renal magnesium wasting. In addition, limited data suggest that CF may impair intestinal magnesium balance. [167]

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Epidemiology

Occurrence in the United States

Although the incidence of hypomagnesemia in the general population has been estimated at less than 2%, some studies have estimated that 75% of Americans do not meet the recommended dietary allowance of magnesium. [168]

In a Mayo Clinic review, magnesium levels of less than 1.7 mg/dL were noted in 13,320 of 65,974 hospitalized adult patients (20.2%). Hypomagnesemia was common in patients with hematologic/oncologicl disorders. [169]

The risk of hypomagnesemia can be summarized as follows:

Although no comprehensive studies have addressed the actual incidence of hypomagnesemia stratified by age group, neonates may be more predisposed to develop the condition. The mechanism for this is unknown, although several studies suggest that neonates have an increased requirement for intracellular magnesium in growing tissues.

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Patient Education

Patients should be counseled regarding modification of risks of hypomagnesemia. Such modifications may include maintaining a proper diet, ceasing alcohol consumption, improving control of diabetes, and taking supplements if the cause of hypomagnesemia is still present.

For patient education information, see the Magnesium - Uses, Side Effects, and More, as well as the Magnesium fact sheet from the National Institutes of Health Office of Dietary Supplements. [110]

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Prognosis

Hypomagnesemia has been linked to poor outcome in several different patient populations. In a study of 21,534 patients on maintenance dialysis, patients with the lowest serum magnesium levels (< 1.30 mEq/L) were at highest risk for death (hazard ratio, 1.63; 95% confidence interval, 1.30-1.96). [170]

Hypomagnesemia is a common development in critically ill sepsis patients, and indicates a poor prognosis. Although evidence is derived largely from observational studies, it shows a significant association between hypomagnesemia and increased need for mechanical ventilation, prolonged intensive care unit stays, and increased mortality in this patient population. [171]

In a Mayo Clinic review of 65,974 hospitalized adult patients, hypomagnesemia on admission was associated with increased in-hospital mortality. Death rates were 2.2% in patients with magnesium levels of 1.5-1.69 mg/dL and 2.4% in those with levels below 1.5 mg/dL; by comparison, mortality in patients with levels of 1.7-1.89 mg/dL were 1.8%. [169]

Hypomagnesemia has been associated with increased risk for severe disease and death in patients with COVID-19. [172] In a study of 1064 patients hospitalized with COVID-19, Guerrero-Romero et al reported that a magnesium-to-calcium ratio ≤0.20 was a biomarker for increased mortality risk in patients with severe COVID-19 disease. [173]

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Author

Ahmed I Kamal, MD, MSc, PhD, FISN Assistant Professor in Transplant Nephrology, Medical University of South Carolina College of Medicine; Assistant Professor of Nephrology, Mansoura Urology and Nephrology Center, Mansour University Faculty of Medicine, Egypt

Ahmed I Kamal, MD, MSc, PhD, FISN is a member of the following medical societies: American Society of Nephrology, Egyptian Society of Nephrology and Transplantation, International Society of Nephrology

Disclosure: Nothing to disclose.

Coauthor(s)

Tibor Fulop, MD, PhD, FACP, FASN Professor of Medicine, Department of Medicine, Division of Nephrology, Medical University of South Carolina College of Medicine; Attending Physician, Medical Services, Ralph H Johnson VA Medical Center

Tibor Fulop, MD, PhD, FACP, FASN is a member of the following medical societies: American Academy of Urgent Care Medicine, American College of Physicians, American Society of Hypertension, American Society of Nephrology, International Society for Apheresis, International Society for Hemodialysis, Magyar Orvosi Kamara (Hungarian Chamber of Medicine)

Disclosure: Nothing to disclose.

Chief Editor

Vecihi Batuman, MD, FASN Professor of Medicine, Section of Nephrology-Hypertension, Deming Department of Medicine, Tulane University School of Medicine

Vecihi Batuman, MD, FASN is a member of the following medical societies: American College of Physicians, American Society of Hypertension, American Society of Nephrology, Southern Society for Clinical Investigation

Disclosure: Nothing to disclose.

Additional Contributors

Mohit Agarwal, MBBS Assistant Professor, Division of Nephrology, Medical College of Wisconsin

Disclosure: Nothing to disclose.

Krishna C Keri, MD, MBBS Fellow in Nephrology and Hypertension, Department of Internal Medicine, Medical College of Wisconsin

Krishna C Keri, MD, MBBS is a member of the following medical societies: American College of Physicians

Disclosure: Nothing to disclose.

Acknowledgements

Mahendra Agraharkar, MD, MBBS, FACP, FASN Clinical Associate Professor of Medicine, Baylor College of Medicine; President and CEO, Space City Associates of Nephrology

Mahendra Agraharkar, MD, MBBS, FACP, FASN is a member of the following medical societies: American College of Physicians, American Society of Nephrology, and National Kidney Foundation

Disclosure: South Shore DaVita Dialysis Center Ownership interest Other

Jeffrey L Arnold, MD, FACEP Chairman, Department of Emergency Medicine, Santa Clara Valley Medical Center

Jeffrey L Arnold, MD, FACEP is a member of the following medical societies: American Academy of Emergency Medicine and American College of Physicians

Disclosure: Nothing to disclose.

Howard A Blumstein, MD, FAAEM Assistant Professor of Surgery, Medical Director, Department of Emergency Medicine, Wake Forest University School of Medicine

Howard A Blumstein, MD, FAAEM is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American Medical Association, Emergency Medicine Residents Association, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) Professor and Chair, First Department of Pediatrics, Athens University Medical School, Aghia Sophia Children's Hospital, Greece; UNESCO Chair on Adolescent Health Care, University of Athens, Greece

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) is a member of the following medical societies: American Academy of Pediatrics, American College of Endocrinology, American College of Physicians, American Pediatric Society, American Society for Clinical Investigation, Association of American Physicians, Endocrine Society, Pediatric Endocrine Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Mark T Fahlen, MD Inc

Mark T Fahlen, MD is a member of the following medical societies: American College of Physicians and Renal Physicians Association

Disclosure: Nothing to disclose.

Enrique Grisoni, MD Associate Professor, Department of Surgery, Division of Pediatric Surgery, University Hospital of Cleveland, Rainbow Babies and Children's Hospital

Disclosure: Nothing to disclose.

Robin R Hemphill, MD, MPH Associate Professor, Director, Quality and Safety, Department of Emergency Medicine, Emory University School of Medicine

Robin R Hemphill, MD, MPH is a member of the following medical societies: American College of Emergency Physicians and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Gunjeet K Kala, MD Clinical Instructor, Division of Pediatric Nephrology, University of Buffalo, State University of New York School of Medicine and Biomedical Sciences, Women and Children's Hospital of Buffalo

Gunjeet K Kala, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Pediatric Nephrology, and American Society of Pediatric Nephrology

Disclosure: Nothing to disclose.

Stephen Kemp, MD, PhD Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas for Medical Sciences College of Medicine, Arkansas Children's Hospital

Stephen Kemp, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Pediatric Society, Endocrine Society, Phi Beta Kappa, Southern Medical Association, and Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Nona P Novello, MD Associate Chair, Department of Emergency Medicine, Franklin Square Hospital

Nona P Novello, MD is a member of the following medical societies: American College of Emergency Physicians and Phi Beta Kappa

Disclosure: Nothing to disclose.

Helbert Rondon-Berrios, MD Nephrology Fellow, Renal-Electrolyte Division, University of Pittsburgh Medical Center

Helbert Rondon-Berrios, MD is a member of the following medical societies: American College of Physicians, American Society of Nephrology, National Kidney Foundation, and Renal Physicians Association

Disclosure: Nothing to disclose.

Karl S Roth, MD Professor and Chair, Department of Pediatrics, Creighton University School of Medicine

Karl S Roth, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American College of Nutrition, American Pediatric Society, American Society for Clinical Nutrition, American Society of Nephrology, Association of American Medical Colleges, Medical Society of Virginia, New York Academy of Sciences, Sigma Xi, Society for Pediatric Research, andSouthern Society for Pediatric Research

Disclosure: Nothing to disclose.

Erik D Schraga, MD Staff Physician, Department of Emergency Medicine, Mills-Peninsula Emergency Medical Associates

Disclosure: Nothing to disclose.

James H Sondheimer, MD, FACP Associate Professor of Medicine, Wayne State University School of Medicine; Medical Director of Hemodialysis, Harper University Hospital at Detroit Medical Center; Medical Director, DaVita Greenview Dialysis (Southfield)

James H Sondheimer, MD, FACP is a member of the following medical societies: American College of Physicians and American Society of Nephrology

Disclosure: Nothing to disclose.

James E Springate, MD Associate Professor of Pediatrics, University of Buffalo, State University of New York School of Medicine and Biomedical Sciences; Attending Physician, Department of Pediatrics, Division of Pediatric Nephrology, Women and Children's Hospital of Buffalo

James E Springate, MD is a member of the following medical societies: American Academy of Pediatrics, American Physiological Society, American Society of Pediatric Nephrology, International Pediatric Transplant Association, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Christie P Thomas, MBBS, FRCP, FASN, FAHA Professor, Department of Internal Medicine, Division of Nephrology, Medical Director, Kidney and Kidney/Pancreas Transplant Program, University of Iowa Hospitals and Clinics

Christie P Thomas, MBBS, FRCP, FASN, FAHA is a member of the following medical societies: American College of Physicians, American Federation for Medical Research, American Heart Association, American Society of Nephrology, American Society of Transplantation, American Thoracic Society, International Society of Nephrology, and Royal College of Physicians

Disclosure: Genzyme Grant/research funds Other

Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.