Magnesium Metabolism Disorders

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?

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• 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?

Laboratory assessment

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%.

Magnesium homeostasis

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

                                                                               —————–        x100

                                                                              (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.