Does this patient have a magnesium metabolism disorder?
Does this patient have a renal magnesium wasting disorder?
In the setting of hypomagnesemia, the consulting nephrologist must determine the following:
Does the patient have clinically significant magnesium depletion?
Are the kidneys conserving magnesium appropriately?
What is the underlying renal diagnosis?
How should the patient be treated?
Does the patient have clinically significant magnesium depletion?
Hypomagnesemia versus magnesium depletion
Hypomagnesemia is traditionally defined as a serum magnesium concentration below the normal reference range. Normal plasma magnesium concentrations typically run between 1.7 and 2.2 mg/dL, 0.75 to 0.95 mmol/L, or 1.5 to 1.9 mEq/L, depending on the units reported (Mg molecular weight=24.3, valence=+2).
However, the serum concentration of magnesium represents less than 1% of total body magnesium, and therefore may not accurately reflect intracellular magnesium levels. As such, many believe that clinically significant magnesium depletion may exist in the setting of a normal serum magnesium concentration. This is supported by a study of alcoholics in whom the magnesium content of mononuclear cells did not correlate with the serum magnesium concentrations. Further, study participants with hypocalcemia (commonly associated with hypomagnesemia – see below) had lower mononuclear cell levels of magnesium compared to those with normocalcemia, which normalized following administration of IV magnesium.
Magnesium depletion, even with a normal serum magnesium level, must therefore be considered in the setting of refractory hypocalcemia or hypokalemia, when there is suspicion for total body magnesium depletion (eg, severe diarrhea or obvious malnutrition).
Clinical Signs and symptoms of magnesium depletion
Identifying and attributing clinical signs and symptoms solely to magnesium depletion can be difficult as it rarely occurs in isolation. Magnesium balance is closely linked to potassium and calcium regulation and is similarly affected by various disease states (eg, diarrheal electrolyte losses). Further, magnesium plays various critical roles in the body, so that depletion can manifest in multiple, sometimes subtle ways.
Magnesium is involved in all reactions requiring adenosine triphosphate (ATP), DNA transcription, RNA translation, and is important in nerve conduction, and ion transport, particularly calcium. The most common clinically significant manifestations of magnesium depletion include the following:
Hypocalcemia. Hypocalcemia is among the most common manifestations of severe hypomagnesemia. This is believed to be secondary to both inhibition of parathyroid hormone (PTH) release, as well as end-organ PTH resistance.
Hypokalemia. Hypokalemia has been reported in more than 50% of those with detectable hypomagnesemia. Magnesium deficiency exacerbates potassium wasting by increasing distal potassium secretion. A decrease in intracellular magnesium (associated with overall magnesium depletion), releases the magnesium-related inhibition of ROMK channels (a rectifying outward potassium channel responsible for potassium secretion) and increases potassium secretion. Importantly, magnesium deficiency alone does not necessarily lead to hypokalemia and requires either an increase in distal sodium delivery or elevated aldosterone levels.
Neuromuscular abnormalities. Increased neuromuscular irritability has been described in isolated hypomagnesemia. This ranges from a positive Trousseau’s sign (spasm in wrist and forearm muscles following inflation of a blood pressure cuff) and Chvostek’s signs (contraction of the facial muscles with external percussion of the facial nerve), to nystagmus, tetany, and seizures. Less apparent findings may include generalized weakness and fatigue.
Cardiac abnormalities. Interference with ATP production in the cardiac myocyte may lead to lower intracellular potassium concentrations with subsequent cell depolarization and reduction of the action potential threshold. Intracellular hypokalemia may also slow the speed of repolarization of the membrane.
Secondary electrical abnormalities are seen and include prominent T waves and widened QRS complex with mild magnesium depletion, and prolongation of the PR interval, progressive widening of the QRS complex, diminution of the T wave, and prolonged QT interval with more significant hypomagnesemia. Ventricular arrhythmias may also be seen, including torsades de pointes. Of note, hypomagnesemia may exacerbate drug-induced prolongation of the QT interval. Hypomagnesemia has notably been associated with dysrhythmias in the setting of acute ischemic heart disease and the use of cardiopulmonary bypass.
Are the kidneys conserving magnesium appropriately?
Simple laboratory testing can confirm if renal wasting of Mg+2 is present. The logic of this laboratory assessment is rooted in basic magnesium homeostasis (see below). Testing should include:
A24-hour urine collection to estimate total daily magnesium excretion. This depends upon magnesium intake, though in the setting of hypomagnesemia, daily excretion should be less than 30mg; and/or
Calculation of the fractional excretion of magnesium (FeMg). In the setting of hypomagnesemia, the FeMg should drop to less than 2%, but can fall to <0.5%.
Under normal physiologic circumstances, net magnesium balance is determined by the product of oral intake and intestinal absorption,minus gastrointestinal loses and renal excretion. In a typical diet, 360 mg of magnesium is ingested, 120 mg is absorbed in the small bowel, and an additional 20 mg is absorbed in the large bowel. This is buffered by 40 mg of magnesium loss from intestinal secretions, leaving a potential positive magnesium balance of 100 mg. The kidneys determine the final balance by regulating the fractional excretion of magnesium, or the amount of magnesium reabsorbed from that filtered.
In the setting of magnesium depletion, bone is the principle extracellular reservoir available to buffer magnesium loss. However,bone does not readily release magnesium into the extracellular compartment, leaving the body vulnerable to small changes in serum magnesium, and again reliant upon the kidney to maintain normal serum magnesium concentrations.
Magnesium resides in two compartments. Ninety-nine percent is localized intracellularly, with the remaining approximately 1% found in the extracellular space, and it exists in three states. Ionized magnesium, the only physiologically active form of magnesium, represents 60 to 70% of total body magnesium, while 30% of magnesium is protein bound, and 10% is complexed with serum anions.
There is currently no described role for laboratory reporting of ionized magnesium (as compared to ionized calcium). However, when assessing appropriate renal handling of magnesium, it is important to note that only non-protein bound magnesium is freely filtered, which is approximately 70% of the measured plasma magnesium concentration.
Using the average daily intake cited above, the kidneys are responsible for eliminating 100 mg of absorbed magnesium in the urine in order to maintain steady state. Under typical conditions, excreting 100 mg of Mg would require a FeMg of between around 4%. For example, in a patient with a serum magnesium concentration of 2.1 mg/dL and a GFR of 110mL/min, presuming 70% is unbound to protein, 2,328 mg of magnesium are filtered each day. In order to eliminate 100mg of Mg+2, 96% of the filtered magnesium must be reabsorbed, a fractional excretion of magnesium of 4%.
Fractional excretion of magnesium (FeMg)= UMg x PCr
(0.7 x PMg) x UCr
What is the underlying renal diagnosis?
Renal magnesium wasting disorders may be considered in two broad categories: primary and secondary. These can often be distinguished by history alone. Primary disorders include inherited defects in tubular transport associated with various clinical syndromes and complex laboratory abnormalities, and in many cases can be ascribed to specific tubular defects. Secondary disorders, such as drug induced magnesium wasting, generally have a more definable onset and are often anticipated and diagnosed by routine laboratory testing. The pathophysiologies of these disorders are generally less well defined. Basic knowledge of renal Mg+2 handling is helpful to understanding both primary and secondary disorders.
Proton pump inhibitors (PPIs) have been associated with both community and hospital acquired hypomagnesemia (a relatively rare occurrence in about 1% of patients taking PPIs) especially in those patients taking diuretics or with another risk factor for magnesium wasting (eg, cisplatin therapy). Although the mechanism of how PPIs may lead to hypomagnesemia is not clear, emerging evidence supports the idea that PPIs may inhibit intestinal absorption since urine magnesium levels were low in many patients. The PPIs may inhibit active magnesium (Mg) absorption by interfering with transcellular transient receptor potential melastatin-6 and -7 (TRPM 6 and 7) channels. More recent cell culture studies have suggested concomitant inhibition of passive Mg absorption by omeprazole. PPI-induced hypomagnesemia resolves quickly with cessation of the drugs but typically is difficult to treat with just oral or intravenous magnesium replacement.
Magnesium handling in the nephron
The vast majority of filtered Mg+2 is reabsorbed. Approximately 10-20% occurs in the proximal tubule, 70% in the thick ascending limb (TAL), and 10% in the distal convoluted tubule (DCT) where Mg+2 excretion is most highly regulated. The latter two segments are best understood, and thought to be the most important in Mg+2 homeostasis.
The Thick Ascending Limb
In the thick ascending limb (TAL), Mg+2 reabsorption is passive and paracellular, and often linked to sodium (Na+) and calcium (Ca+2) reabsorption. As such, tubular defects affecting Mg+2 reabsorption in the TAL are commonly associated with increased Na+ delivery to the distal nephron, leading to mild volume depletion and down stream renin mediated aldosterone release. TAL defects are therefore commonly associated with secondary metabolic alkalosis and potassium excretion. Further, hypercalciuria and hypocalcemia are often present as well.
Magnesium reabsorption in the TAL begins with the transcellular Na+/K+ gradients established by the basolateral Na-K-ATPase. This gradient drives the Na-K-2Cl transporter (the loop diuretic sensitive transporter) on the luminal side of the tubular epithelium. Intracellular potassium then diffuses back into the tubule through the ROMKchannel. Chloride leaves via the basolateral CLC-Kbchannel. This creates a relative small positive charge in the lumen compared to the intracellular and paracellular spaces.
The charge gradient is further augmented by paracellular leak of Na+ back into the tubular lumen through a paracellular tight-junction protein complex composed of proteins claudin-16 and claudin-19that also has some permeability to Mg+2. Mg+2 and Ca+2 reabsorption in the TAL are inhibited by activation of the calcium sensing receptor (CaSR). Defects in each of the proteins listed have been linked to various syndromes of hypomagnesemia (see primary disorders, TAL below).
Distal Convoluted Tubule
The distal convoluted tubule (DCT)is the most distal nephron segment responsible for Mg+2 reabsorption, and is the only site of active Mg+2 reabsorption. As in the TAL, Mg+2 reabsorption is dependent upon an electrical gradient between the intracellular and paracellular spaces, and the tubule, with a positively charged lumen driving the cellular in-flux of Mg+2.
As compared to Mg+2 reabsorption in the TAL, where disruption often leads to urinary calcium loss, problems with Mg+2 resorption in the DCT are not generally associated with hypercalciuria. In fact, mild volume depletion from Na+ loss may stimulate avid Na+ reabsorption in the TAL with a secondary increase in Ca+2 resorption and hypocalciuria. However, as with TAL defects, distal Na+ delivery is often increased, leading to secondary alkalosis and increased urinary potassium loses.
Recently characterized proteins appear to be important in DCT Mg+2 reabsorption. Defects in each have been ascribed to various disease states. The functional relationship between these proteins and the contribution each make to Mg+2 reabsorption is not well defined. Transient receptor potential channel melastatin member 6 (TRPM6), an epithelial Mg+2 channel expressed on the luminal surface of DCT cells and intestine appears to be vital for Mg+2 resorption. Epidermal growth factor (EGF) activates TRPM6 by shuttling it to the plasma membrane. The thiazide sensitive Na/Cl cotransporter (NCC) coded by SLC12A3 gene, and the Shaker-related voltage-gated K channel (Kv1.1), co-localize with TRPM6, and likely play separate rolls in the hyperpolarization of the cell that drives Mg+2 influx.
Several other proteins have been found to be important in Mg+2 reabsorption. These include FXYD2 and HNF1B, which code for subunits of the Na/K-ATPase, and iATP-sensitive inward rectifier potassium channel 10 (Kir4.1), which resides on the basolateral membrane and appears to allow K recycling across the basolateral membrane in order to sustain Na/K-ATPase activity.
What are the relevant clinical and laboratory findings associated with primary renal magnesium wasting disorders?
Primary renal magnesium wasting disorders are diagnoses of exclusion, and based upon inappropriate urinary magnesium losses in the setting of hypomagnesemia (eg, FeMg>2%). As above, they are commonly associated with abnormalities in serum potassium, bicarbonate, and calcium concentrations, as well as urinary calcium excretion, which is often, but not always, a distinguishing clinical characteristic. Disorders of the TAL (Table I) are commonly associated with hypercalciuria, hypokalemia, and metabolic alkalosis. Disorders of the DCT (Table II) are commonly associated with hypo calciuria, hypokalmeia, and metabolic alkalosis.
|Disorder, inheritance||Protein Defect (gene)||Laboratory and Clinical Findings||SMg||UMg||SCa||UCa|
|Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), autosomal recessive.||Claudin-16, (CLDN16) Claudin-19, (CLDN19)||Profound renal Mg+2 and Ca+2 wasting are seen with secondary nephrocalcinosis and progressive kidney failure. FHHNC presents in early infancy/childhood with symptomatic hypocalcemia. Symptoms may include frequent urinary tract infections, polyuria and polydipsia, nephrolithiasis, adominal pain, seizures, tetany, and failure to thrive. Ocular manifestations appear unique to those with CLDN19 mutations. The genetic mutations are heterogeneous with various phenotypes. Of those with complete-loss-of-function mutations, approximately 70% reach ESKD by age 20, as compared to 25% for those with partial-loss-of-function mutations.||−||+||−||+|
|Bartter Syndrome, autosomal recessive||Various proteins may be involved: Na-K-2Cl cotransporter (SLC12A1), type 1; ROMK Luminal potassium channel (KCNJ1), type 2; CLC-Kb Basolateral chloride channel(CLCNKB), type III Barttin beta-subunit of the chloride channel (BSND), type IV; CaSR Calcium sensing receptor (CASR), type V.||Renal NaCl and Ca+2 wasting are seen with secondary hypokalemia and metabolic alkalosis. Many of the downstream electrolyte abnormalities appear to be driven by prostoglandin mediated renin release, a distinguishing feature of Barrter’s as compared to Gitelman Syndrome (see below). Bartter Syndrome represents a heterogenious group of genetic and molecular defects, among which Mg+2 wasting is variable, and generally mild. The presentation is also variable, as the phenotypic features vary widely based upon the protein involved and the nature of the mutation. Bartter Syndrome Types 1 and 2 are associated the more severe phenotypes, often presenting in the antenal period with polyhydramnios. Common features include polyuria, polydipsia, growth retardation, and occasionally failure to thrive and nephrocalcinosis. Type IV is associated with sensorineural hearing loss. Barter’s can be differentiated from diuretic abuse in some cases by screening of the urine for traces of diuretic. Patients are generally euvolemic, though normo- to hypo-tensive, with urine chloride (UCl) >40mEq/L, as compared to surreptitious vomitting where UCl is more typically <20mEq.||+/−||+/−||wnl||+|
− = low; + =high; +/−=variable; wnl=within normal limits
|Disorder, Inheritance||Protein Defect (gene)||Laboratory and Clinical Findings||SMg||UMg||SCa||UCa|
|Gitelman Syndrome, autosomal recessive||NCC Thiazide-sensitive sodium chloride cotransporter (SCL12A3)||Renal NaCl and Mg+2 wasting are seen with secondary hypomagnesemia, hypocalciuria, hypokalemia and metabolic alkalosis. Gitelman Syndrome most often presents after 6 years of age, and is not uncommonly first diagnosed as an adult. It can present with tetany, paraesthesias, fatigue/weakness, cramping, aches, polyuria, aches, nocturia, polydipsia, and low blood pressures. It has been associated with chondrocalcinosis. Cardiac arrest has been reported due to electroylyte abnormalities. The prognosis is generally good. As with Bartter Syndrom, Gittelman’s may in some cases be differentiated from diuretic abuse by urine diuretic screen. Patients are also generally euvolemic with UCl >40mEq/L, as compared to surreptitious vomitting.||−||+||wnl||minus;|
|Familial hypomagnesemia with Secondary hypocalcemia (HSH), autosomal recessive||TRPM6 Transient Receptor Potential Channel Melastatin Member 6 (TRPM6)||Renal Mg+2 wasting is seen along with poor Mg+2 absorption in the intestine (TRPM6 is expressed in the intestine) leading to severe hypomagnesemia with levels <0.4mmol/L. Hypomagnesemia related hypocalcemia is present as well (likely due to low PTH). The condition presents at just a couple weeks of age with neuromuscular excitability, spasms, tetany, and convulsions. Untreated, it may lead to permanent neurologic impairment and death.||−||+||−||wnl|
|Hypomagnesemia with hypocalciuria, autosomal dominant||Gamma-subunit of basolateral Na/K-ATPase (FXYD2); HNF1B transcription factor linked to regulation of the FXYD2 gene (HNF1B)||Renal Mg+2 wasting with secondary hypocalciuria. Patients present with convulsions, but may be asymptomatic, and may develop chondrocalcinosis at an adult age. Affected persons may present with recurrent muscle cramps, tetany, tremor, muscle weakness, cerebellar atrophy, and myokymia.||−||+||wnl||−|
|Isolated renal hypomagnesemia (IRH), autosomal recessive||Pro-Epidermal Growth Factor (EGF)||Renal Mg+2 wasting with no detectable abnormality in urinary calcium excretion(as compared to HSH). Presented in childhood with seizures, psychomotor retardation, and mental retardation in adulthood.||−||+||wnl||wnl|
|Autosomal dominant hypomagnesemia||Kv1.1 voltage-gated K+ channel of luminal membrane (KCNA1)||Renal Mg+2 wasting without obvious urinary or serum calcium abnormality. Detected in infancy with recurrent muscles cramps, tremor, weakness, tetany, cerebellar atrophy, and myokymia.||−||+||wnl||wnl|
|Epilepsy, ataxia, sensorineurol deafness, tubulopathy (EAST, aka SeSAME)||Kir4.1 K+ channel of basolateral membrane (KCNJ10)||Renal NaCl and Mg+2 wasting with hypokalemia, metabolic alkalosis, and hyopocalciuria. Presents in infancy with epilepsy, ataxia, sensorineural deafness, and polyuria.||−||+||wnl||−|
− = low; + =high; wnl=within normal limits
What are the relevant clinical and laboratory findings associated with secondary renal magnesium wasting disorders?
The etiology of secondary Mg+2 wasting is often apparent by history. Associated lab abnormalities and clinical characteristics vary (Table III).
|Etiology, mechanism of action||Laboratory and Clinical Findings|
|Loop diuretics.Blockade of the Na-K-2Cl cotransporter in the TAL reduces the intracellular concentration of K+, and the subsequent backleak of K+ through the ROMK channel, limiting the mechanism by which the positive charge gradient driving Mg+2 resorption is established between tubular, and intra- and para-cellular compartments.||Hypomagnesemia is a variable, and a relatively uncommon finding for a drug with such a clear pathophysiologic mechanism. Renal NaCl and Mg+2 wasting are seen, and may be associated with hypomagnesemia, hypercalciuria, hypokalemia, and metabolic alkalosis. Volume loss and electrolyte abnormalities are generally limited by augmented proximal sodium reabsoption. Generally less severe than Bartter Syndrome, and may be distinguised using a urinary diuretic screen. If drug is active in the body, urine chloride may be >40mEq/L. Once drug wears off, this is expected to drop with volume contraction.|
|Thiazide diuretics. Although thiazides are known to block NCC thiazide-sensitive sodium chloride cotransporter in the DCT, the exact downstream mechanism of Mg+2 wasting is uncertain.||Renal NaCl and Mg+2 wasting may be seen, associated with variable degrees of hypomagnesemia, hypocalciuria, hypokalemia and metabolic alkalosis. Volume loss and electrolyte abnormalities are generally limited by augmented proximal sodium reabsoption. Thiazides may be differentiated from Gitelman Syndrome using a urinary diuretic screen. If drug is active, urine chloride will be >40mEq/L. Once drug wears off, one expects a drop in urine chloride consistent with volume contraction.|
|AminoglycosidesThe mechanism for Mg+2 wasting is unknown, but may be due to the drugs known direct tubular toxicity.||Mg+2 wasting may occur after just a brief exposure but remain clinically inapparent. Magnesium depletion may be delayed days or weeks into therapy, even surfacing after discontinuation of therapy. It may persist for weeks to months.|
|AmphotericinThe drug is a direct tubular toxin.||Mg+2 wasting appears to be dose dependent, though the effect may pleateau with extended exposure. Mg+2 wasting appears to be reversible with discontinuation of the drug.|
|CisplatinThe drug is a direct tubular toxin in the proximal and distal tubules.||Mg+2 wasting is dose dependent, may persist for years, and may ultimately be irreversible. Hypomagnesemia may perpetuate the nephrotoxicity of this drug.|
|Calcineurin Inhibitors (CNIs)CNIs are believed to down-regulate TRPM6 Mg+2 channels in the DCT.||Mg+2 wasting is seen in solid organ and bone marrow transplant patients with both cyclosporine and tacrolimus. Hypomagnesemia often persists despite aggressive Mg+2 replacement.|
|CetuximabInhibits the EGF-receptor, supressing expression of TRPM6, the Mg+2 permeable ion channels on the luminal surface of the DCT.||Renal Mg+2 wasting may be severe requiring aggressive inravenous repletion, but is reversible with discontinuation of the drug.|
|Volume expansionTubular flow is increased which may decrease NaCl reabsorption, thereby inhibiting Mg+2 reabsorption.||May be seen with aggressive administration of normal saline.|
|Acute Tubular Necrosis (ATN)Due to a combination of tubular dysfunction from tubular injury, and increased flow from reduced NaCl reabsorption.||May occur in the recovery/diuretic phase of ATN.|
|Renal TransplantLikely multifactorial, due to a combination of tubular dysfunction from tubular injury, increased flow from reduced NaCl reabsorption and IVF, with likely some contribution of CNIs.||As per ATN, may occur following ischemia reperfusion in the recovery/diuretic phase. Theoretical contributors include aggressive intravenous hydration following kidney transplant and reduction in TRPM6 expression in the DCT from calcineurin inhibitors.|
|Post-obstructive diuresisDue to a combination of tubular dysfunction from tubular injury, and increased flow from reduced NaCl reabsorption.||As per ATN, may occur following relief of the obstruction, prior to full recovery of tubular function.|
|Diabetes, type IIFiltered Mg+2 load may be augmented by hyperfiltration and osmotic diuresis, while concurrently reabsorption is reduced by hypoinsulinemia.||A common finding in type-2 diabetics, with multiple potential mechanisms. Treatment is recommended.|
|Alcohol useCauses reversible tubular dysfunction.||Renal Mg+2 wasting in the setting of chronic alcohol use is often concurrent with poor Mg+2 intake, pancreatitis (that can sequester Mg+2), and diarrhea. Tubular dysfunction may resolve weeks after alcohol cessation.|
|ChelationMay bind free anions.||Can occur in the setting of pancreatitis and intravenous administration of citrated solutions.|
|HypercalcemiaActivates the CaSR in the TAL, blocking the ROMK channel, shutting down the N-K-2Cl pump.|
|Hungry Bone SyndromePresumed secondary to rapid deposition in bone matrix following parathyroidectomy.|
What tests to perform?
A full blood chemistry panel
This should include serum sodium (Na+), potassium (K+), chloride (Cl-), bicarbonate (HCO3-), blood urea nitrogen (BUN), and creatinine (Cr). Primary renal wasting disorders are commonly associated with hypokalemia, metabolic alkalosis, and those affecting the TAL may be associated with hypocalcemia. Importantly however, hypocalcemia and hypokalemia are very common in hypomagnesemia regardless of the underlying cause.
Urinary magnesium, calcium, and chloride – Fractional excretion of magnesium and daily calcium should be estimated.
FeMg+2 >2% in the setting of hypomagnesemia is consistent with renal magnesium wasting. Daily urinary calcium excretion >200-250 mg is considered hypercalciuria and is more often associated with Mg+2 resorption disorders of the TAL. Urinary chloride (UCl) <20 mEq/L suggests volume depletion. This may be helpful in assessing normotensive patients with hypokalemia and metabolic alkalosis to differentiate vomiting (UCl<20 mEq/L), a state of relative volume depletion, from Gitelmans or Bartter syndromes where patients generally maintain euvolemia (UCl>40 mEq/L) through oral intake.
UCl is variable in the setting of diuretic use. It will be high in those who have recently taken diuretics, due to the obligate NaCl loss. However, it is likely to be low once the diuretic effect has worn off, or if the patient is volume depleted.
Urinary diuretic screen
This can be used to differentiate between diuretic use/abuse and primary renal Mg+2 wasting disorders in normotensive patients with hypokalemia and metabolic acidosis.
Renal ultrasound or KUB x-ray film
Renal imaging may demonstrate nephrocalcinosis or nephrolithisasis, further supporting a diagnosis of hypercalciuria.
In patients and families who are suspected of having a primary renal wasting disorder, genetic testing may be available.
How should patients with renal magnesium wasting be managed?
Stabilize the patient
The urgency and treatment prescription for hypomagnesemia requires a complete assessment of the patient, including investigation of clinically significant sequelae of hypomagnesemia including EKG findings, muscle weakness, tetany, convulsions, and other electrolyte abnormalities including hypokalemia and hypocalcemia.
Those with associated cardiac arrhythmias and seizure activity require emergent attention, including intravenous magnesium repletion and cardiac monitoring. This is particularly important in those with a history of cardiac ischemia, arrhythmia, or structural heart disease. Hypokalemia and hypocalcemia may be difficult to correct until magnesium is replete, but correction of critical hypokalemia and hypocalcemia should not be delayed while magnesium is restored.
Acute symptomatic hypomagnesemia needs to be repleted intravenously. It has been suggested that those with hypomagnesemic-hypokalemic ventricular arrhythmias or tetany be given 8-16 mEq in an intravenous bolus over 5-10 minutes, and that those with moderate to severe magnesium deficiency be given 50 mEq over 8 to 24 hours, repeating as necessary to keep the plasma Mg+2 concentration >1.0mg/dL (0.8mEq/L). Magnesium sulfate, among the more common intravenous preparations of magnesium, has 98.6 mg of elemental magnesium in 1gram, or 8.12 mEq of elemental magnesium.
After the initial rapid correction of critical hypomagnesemia, ongoing Mg+2 replacement should be more gradual. Serum magnesium is a potent down regulator of magnesium resorption by the kidney, and so rapid repletion of serum magnesium may inhibit renal resorption with unintended renal wasting prior to restoration of total body magnesium.
For those with more modest, asymptomatic hypomagnesemia, oral slow-release therapy is preferred. Available magnesium salt preparations include magnesium-chloride, -lactate, -gluconate, -sulfate, and -oxide. The required dose of each varies, as each preparation has both a unique magnesium content and bioavailability.
In principle, 1g of elemental magnesium equals 83.3mEq or 41.1 mmol. However, bioavailability may limit the practical dosing required for each preparation. For example, magnesium oxide has among the highest elemental magnesium concentrations (60%), but poor bioavailability. Meanwhile, magnesium chloride and lactate contain less elemental magnesium than magnesium oxide (12%), but have notably better bioavailability. Both of the latter two come in slow-release preparations.
It is suggested that those with moderate depletion take 10 to 15mEq of Mg+2 two to three times per day, and that those with mild depletion may take 10-15mEq one to two times per day. Oral magnesium repletion can be complicated by diarrhea, which may be reduced by dividing doses throughout the day.
Preventing Magnesium Loss
In addition to magnesium repletion, one should consider the feasibility and safety of trying to reduce ongoing renal Mg+2 wasting. Factors to consider include the magnitude and expected duration of ongoing losses, concurrent electrolyte abnormalities, and the reversibility of the underlying cause.
Potassium sparing diuretics. Aldosterone antagonists and amiloride have been used to augment distal Mg+2 reabsoption, and to block distal K+ and H+ excretion in those with described tubular defects such as Barter’s and Gitelman’s Syndromes. Up to 40mg of amiloride or 300 mg of spironolactone per day have been used, though it is logical to begin at lower doses.
Offending drugs. In cases of Mg+2 wasting where a specific drug is implicated, consideration should be given to stopping the drug. In cases where the causative agent should/cannot be stopped (eg, CNI immediately following kidney transplantation or in a patient with significant volume overload in need of loop diuretic), one may consider concurrent use of a potassium sparing diuretic, in addition to standard electrolyte repletion.
Cyclooxygenase inhibition. It is worth mentioning that NSAID therapy (eg, indomethacin) and COX-2 inhibitors have been used to treat patients with specific forms of Bartter’s that appear to be mediated by prostaglandin-induced renin release.
Therapy is generally directed toward minimizing K+ loss, with no clear role for treating Mg+2 wasting, which is not generally a significant problem in Bartter’s syndrome. There is no described role for cyclooxygenase inhibition in treating Gitelman syndrome, which does not appear to be mediated by prostaglandins. Well described risks of chronic NSAID therapies include gastric ulcers, gastritis, and progressive chronic kidney disease.
ACE-Inhibitors (ACEI) and Angiotensin Receptor Blockers (ARBs). ACEI and ARBs may be also be helpful to reduce renin driven aldosterone release and secondary K+ and H+ excretion. The practical use of these agents may be limited for those with lower blood pressures, and there does not appear to be a clear role in reducing Mg+ wasting specifically.
Are there clinical practice guidelines to inform decision making?
There are no clinical practice guidelines focused on magnesium disorders.
DRG 296: Nutritional and miscellaneous metabolic disorders
Typical length of stay depends upon underlying disorder. Most patients can be treated as outpatients, in the emergency department or at an infusion center
What is the evidence?
Agus, AS. “Hypomagnesemia”. J Am Soc Nephrol. vol. 10. 1999. pp. 1616-1622.
Alexander, R, Joenderop, J, Bindels. “Molecular determinants of magnesium homeostasis: insights from human disease”. J Am Soc Nephrol. vol. 19. 2008. pp. 1451-1458.
Cao, Y, Liao, C, Tan, A, Liu, L, Gao, F. “Meta-analysis of incidence and risk of hypomagnesemia with cetuximab for advanced cancer”. Chemotherapy. vol. 56. 2010. pp. 459-465.
Conrad, M, Hou, J, Weber, S, Dotsch, J, Kari, J, Seeman, T, Kuwertz-Broking, E, Peco-Antic, A, Tasic, V, Dittrich, K, Alshaya, H, von Vigier, R, Gallati, S, Goodenough, D, Schaller, A. “CLDN16 genotype predicts renal decline in familial hypomagnesemia with hypercalciuria and nephrocalcinosis”. J Am Soc Nephrol. vol. 19. 2008. pp. 171-81.
Danziger, J, William, JH, Scott, DJ, Lee, J, Lehman, LW, Mark, RG, Howell, MD, Celi, LA, Mukamal, KJ. “Proton pump inhibitor use is associated with low serum magnesium concentrations”. Kidney Int. vol. 83. 2013. pp. 692-699.
Dietrich, A, Chubanox, V, Gudermann, T. “Renal TRPathies”. J Am Soc Nephrol. vol. 21. 2010. pp. 736-744.
Elliott, C, Newman, N, Madan, A. “Gentamicin effects on urinary electrolyte excretion in healthy subjects”. Clin Pharmacol Ther. vol. 67. 2000. pp. 16-21.
Firoz, M, Graber, M. “Bioavailability of US Commercial magnesium preparations”. Magnes Res. vol. 14. 2001. pp. 257-262.
Gamba, G, Friedman, P. “Thick ascending limb: the Na(+):K(+):2Cl(−) co-transporter, NKCC2, and the calcium-sensing receptor CaSr”. Pflugers Arch. vol. 458. 2009. pp. 61-76.
Glaudemans, B, Knoers, N, Hoenderop, J, Binder, R. “New molecular players facilitating Mg+2 reabsorption in the distal convoluted tubule”. Kidney Int. vol. 77. 2010. pp. 17-22.
Goren, MP. “Cisplatin nephrotoxicty affects magnesium and calcium metabolism”. Med Pediatr Oncol. vol. 41. 2003. pp. 186-189.
Graziani, G, Fedeli, C, Moroni, L, Cosmai, L, Badalamenti, S, Ponticelli, C. “Gitelman syndrome: pathophysiological and clinical aspects”. QJM. vol. 103. 2010. pp. 741-748.
Hene, R, Koomans, H, Dorhout Mees, E, Verhoef, G, Boer, P. “Correction of hypokalemia in Bartter's syndrome by enalapril”. Am J Kidney Dis. vol. 9. 1987. pp. 200-205.
Knoers, N. “Inherited forms of renal hypomagnesemia: an update”. Pediatr Nephrol. vol. 24. 2009. pp. 697-705.
“Dietary Supplement Fact Sheet: Magnesium”.
Pham, PC, Pham, PM, Pham, S, Miller, J, Pham, PT. “Hypomagnesemia in patients with Type 2 diabetes”. Clin J Am Soc Nephrol. vol. 2. 2007. pp. 366-373.
Ranade, V, Somberg, J. “Bioavailability and pharmacokinetics of magnesium after administration of magnesium salts to humans”. Am J Ther. vol. 8. 2001. pp. 345-357.
Reinalter, S, Jeck, N, Brochhausen, C, Watzer, B, Nusing, R, Seyberth, H, Komhoff, M. “Role of cyclooxygenase-2 in hyperprostaglandin E syndrome/antenatal Bartter syndrome”. Kidney Int. vol. 62. 2002. pp. 253-260.
Rombola, C, Ferrari, D, Minetti, M. “Correction of hypokalemia with antialdosterone therapy in Gitelman's syndrome”. Am J Nephrol. vol. 12. 1994. pp. 127-135.
Ryzen, E, Nelson, TA, Rude, RK. “Low blood mononuclear cell magnesium content and hypocalcemia in normomagnesemic patients”. West J Med. vol. 147. 1987. pp. 549-553.
Seyberth, H. “An Improved terminology and classification of Bartter-like syndromes”. Nat Clin Pract Nephrol. vol. 4. 2008. pp. 560-567.
San-Cristobal, P, Dimke, H, Hoenderop, J, Bindels, R. “Novel molecular pathways in renal Mg+2 transport: a guided tour along the nephron”. Curr Opin Nephrol Hypertens. vol. 19. 2010. pp. 456-62.
Toh, JWT, Ong, E, Wilson, R. “Hypomagnesemia associated with long-term use of proton pump inhibitors”. Gastroenterol Rep. vol. 3. 2015. pp. 243-253.
Topf, J, Murray, P. “Hypomagnesemia and hypermagnesemia”. Rev Endocr Metab Disord. vol. 4. 2003. pp. 195-206.
Vaisbich, M, Fujimura, M, Koch, V. “Bartter syndrome: benefits and side effects of long-term treatment”. Pediatr Nephrol. vol. 19. 2004. pp. 858-863.
Wagner, C. “Disorders of renal magnesium handling explain renal magnesium transport”. J Nephrol. vol. 20. 2007. pp. 507-510.
Weisinger, J, Bellorin-Font, E. “Magnesium and phosphorus”. Lancet. vol. 352. 1998. pp. 391-396.
Copyright © 2017, 2013 Decision Support in Medicine, LLC. All rights reserved.
- Does this patient have a magnesium metabolism disorder?
- Does the patient have clinically significant magnesium depletion?
- Hypomagnesemia versus magnesium depletion
- Clinical Signs and symptoms of magnesium depletion
- Are the kidneys conserving magnesium appropriately?
- Laboratory assessment
- Magnesium homeostasis
- What is the underlying renal diagnosis?
- Magnesium handling in the nephron
- What are the relevant clinical and laboratory findings associated with primary renal magnesium wasting disorders?
- What are the relevant clinical and laboratory findings associated with secondary renal magnesium wasting disorders?
- What tests to perform?
- How should patients with renal magnesium wasting be managed?
- Are there clinical practice guidelines to inform decision making?
- Other considerations
Want to read more?
Please login or register first to view this content.