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Effect of diuretics on magnesium handling by the kidney

Effect of diuretics on magnesium handling by the kidney
Authors:
Alan S L Yu, MB, BChir
Sri G Yarlagadda, MD
Section Editor:
Richard H Sterns, MD
Deputy Editor:
Albert Q Lam, MD
Literature review current through: Jun 2022. | This topic last updated: Mar 24, 2021.

INTRODUCTION — Approximately 2.5 g of magnesium (100 mmol) is filtered by the glomerulus every day. Under normal conditions, 95 percent of the filtered magnesium is reabsorbed, and 5 percent is excreted. Reabsorption of magnesium occurs via both paracellular and transcellular processes. (See "Regulation of magnesium balance".)

Diuretics are widely used in the treatment of hypertension, heart failure, cirrhosis, and kidney diseases. Three types of diuretics are known to influence magnesium homeostasis:

Loop diuretics

Thiazide-type diuretics

Potassium-sparing diuretics

Loop and thiazide diuretics can enhance urinary magnesium losses, although by different mechanisms [1,2], while potassium-sparing diuretics can reduce magnesium excretion. Before the glomerular filtrate reaches the loop of Henle, approximately 15 to 25 percent of the filtered magnesium load is reabsorbed by the proximal tubule. Although the mechanism is not well understood, magnesium reabsorption by the proximal tubule appears to involve a paracellular process that depends upon sodium and water transport. A small lumen-positive potential in the early proximal tubule also adds to the driving force [3]. (See "Regulation of magnesium balance".)

LOOP DIURETICS — Filtered sodium chloride enters the cells in the thick ascending limb of the loop of Henle via Na-K-2Cl cotransporters in the apical (luminal) membrane (figure 1) [4]. Although this process is electrically neutral, some of the reabsorbed potassium leaks back into the lumen to drive further sodium chloride transport. This movement of cationic potassium makes the lumen relatively electropositive, thereby creating an electrical gradient that promotes the passive paracellular (between cells) reabsorption of sodium and divalent cations, such as magnesium and calcium. (See "Diuretics and calcium balance".)

Paracellular magnesium reabsorption appears to be facilitated by the tight junction proteins, claudin-16 and -19. Mutations in the genes encoding these proteins cause familial hypomagnesemic hypercalciuria with nephrocalcinosis [5,6]. (See "Hypomagnesemia: Causes of hypomagnesemia", section on 'Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC)'.)

Loop diuretics act by competing for the chloride site on the Na-K-2Cl cotransporter [4]. Inhibiting sodium chloride reabsorption also inhibits the back leak of potassium and the generation of the lumen-positive potential, thereby decreasing the electrical gradient for magnesium reabsorption and increasing urinary magnesium excretion. Net magnesium transport is inhibited to a greater degree than sodium at any given luminal furosemide concentration because magnesium (as a divalent cation) is influenced by the voltage change to a greater degree than sodium and potassium (which are monovalent cations) [7]. (See "Mechanism of action of diuretics".)

THIAZIDE DIURETICS — Magnesium reabsorption in the distal nephron is thought to occur primarily in the distal convoluted tubule via a transcellular (across cells) mechanism. Entry of filtered magnesium into the cell in this segment is mediated by a channel in the luminal membrane called TRPM6 (transient receptor potential cation channel melastatin) [8]; magnesium entry into the cell is enhanced by the favorable electrochemical gradient across the luminal membrane [9]. There is some evidence that the exit mechanism in the basolateral membrane (which returns the reabsorbed magnesium to the peritubular capillary) could involve a sodium-magnesium exchange [10]. The driving force for this exchange is the low sodium concentration inside the cell (10 to 15 mEq/L) compared with that in the extracellular fluid, thereby favoring sodium entry and subsequent magnesium exit.

The thiazide-type diuretics decrease sodium chloride reabsorption in the distal tubule by inhibiting electroneutral Na-Cl cotransporters in the apical membrane that are responsible for the entry of luminal sodium and chloride into the cell (figure 2) [4]. The effect of thiazide diuretics on magnesium transport may vary with acute or chronic administration. In isolated distal tubular cells, the acute inhibition of entry of sodium chloride leads to increased uptake of magnesium [11]. Chronic administration as is normally encountered clinically, however, tends to increase magnesium excretion [1,2]. This seemingly paradoxical effect may be due to several mechanisms:

Chronic administration of thiazides or the genetic absence of the Na-Cl cotransporters reduces renal expression levels of TRPM6 in mice [12]. This mechanism explains the magnesium wasting seen in Gitelman syndrome, in which a mutation in the distal tubule Na-Cl cotransporter produces a situation equivalent to continuous thiazide diuretic administration. (See "Inherited hypokalemic salt-losing tubulopathies: Pathophysiology and overview of clinical manifestations".)

Chronic administration of thiazides is frequently associated with negative potassium balance and hypokalemia. Hypokalemia may in turn directly inhibit distal tubular cell magnesium uptake, thereby increasing magnesium excretion [11].

POTASSIUM-SPARING DIURETICS — Sodium reabsorption by collecting tubule cells is electrogenic because positively charged sodium is reabsorbed without an anion (figure 3), making the lumen electronegative. This creates an unfavorable electrical gradient that inhibits magnesium reabsorption. Potassium-sparing diuretics (amiloride, triamterene, and spironolactone) decrease sodium entry mediated by epithelial sodium channels in the connecting tubule and cortical collecting tubule [4], an effect that enhances magnesium reabsorption. Thus, these agents decrease magnesium excretion [13,14].

OSMOTIC DIURETICS — Sodium-glucose co-transporter 2 (SGLT2) inhibitors (canagliflozin, dapagliflozin, empagliflozin, and ipragliflozin) are being increasingly used to treat diabetes, heart failure, and diabetic kidney disease. Although they are not formally considered as diuretic agents, their ability to increase luminal glucose concentrations in the proximal tubule can induce an osmotic diuresis. (See "Sodium-glucose co-transporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Mechanism of action'.)

Since approximately 10 to 25 percent of the filtered load of magnesium is reabsorbed in the proximal tubule, it might be expected that SGLT2 inhibitors would lead to urinary loss of magnesium. In practice, however, SGLT2 inhibitors have been observed to induce mild increases in serum magnesium levels [15,16]. The mechanisms for this effect are not well understood. Decreased filtration of magnesium, increased tubular reabsorption, and increased expression of magnesium transporters may play a role.

CLINICAL EFFECTS OF DIURETICS ON MAGNESIUM — Mild magnesium depletion appears to be relatively common after loop or thiazide diuretic therapy [1], and these drugs occasionally produce hypomagnesemia. (See "Hypomagnesemia: Causes of hypomagnesemia", section on 'Renal losses'.)

However, in patients treated with diuretics, the serum magnesium concentration often remains within or near the normal range, possibly because most of the losses come from the cells [14,17]. However, preferential intracellular loss has not been a uniform finding [1].

The incidence and clinical importance of magnesium depletion without hypomagnesemia are uncertain. It has been proposed (although clearly not proven [18]) that these patients may be at increased risk for cardiac arrhythmias, particularly if they are also hypokalemic. (See "Significance of hypomagnesemia in cardiovascular disease".)

SUMMARY

Approximately 2.5 g of magnesium (100 mmol) is filtered by the glomerulus every day. Under normal conditions, 95 percent of the filtered magnesium is reabsorbed, and 5 percent is excreted. Diuretics are widely used in the treatment of hypertension, heart failure, cirrhosis, and kidney diseases. Loop and thiazide diuretics can enhance urinary magnesium losses, although by different mechanisms, while potassium-sparing diuretics can reduce magnesium excretion. (See 'Introduction' above.)

Filtered sodium chloride enters the cells in the thick ascending limb of the loop of Henle via Na-K-2Cl cotransporters in the apical (luminal) membrane (figure 1). Some reabsorbed potassium leaks back into the lumen, making the lumen relatively electropositive and thereby creating an electrical gradient that promotes the passive paracellular (between cells) reabsorption of magnesium. Loop diuretics act by competing for the chloride site on the Na-K-2Cl cotransporter. Inhibiting sodium chloride reabsorption also inhibits the back leak of potassium and the generation of the lumen-positive potential, thereby decreasing the electrical gradient for magnesium reabsorption and increasing urinary magnesium excretion. (See 'Loop diuretics' above.)

Magnesium reabsorption in the distal nephron is thought to occur primarily in the distal convoluted tubule via a transcellular (across cells) mechanism. Entry of filtered magnesium into the cell in this segment is mediated by a channel in the luminal membrane called TRPM6 (transient receptor potential cation channel melastatin). Chronic administration of thiazide diuretics tends to increase magnesium excretion, possibly by reducing renal expression levels of TRPM6 and inducing hypokalemia, which may in turn directly inhibit distal tubular cell magnesium uptake. (See 'Thiazide diuretics' above.)

Sodium reabsorption by collecting tubule cells is electrogenic because positively charged sodium is reabsorbed without an anion (figure 3), making the lumen electronegative. This creates an unfavorable electrical gradient that inhibits magnesium reabsorption. Potassium-sparing diuretics decrease sodium entry mediated by epithelial sodium channels in the connecting tubule and cortical collecting tubule, an effect that enhances magnesium reabsorption. (See 'Potassium-sparing diuretics' above.)

Mild magnesium depletion appears to be relatively common after loop or thiazide diuretic therapy, and these drugs occasionally produce hypomagnesemia. However, in patients treated with diuretics, the serum magnesium concentration often remains within or near the normal range, possibly because most of the losses come from the cells. (See 'Clinical effects of diuretics on magnesium' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Zalman S Agus, MD, who contributed to earlier versions of this topic review.

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