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Home , Hypokalemia, Magnesium deficiency

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Mechanism of in Deficiency

Chou-Long Huang*† and Elizabeth Kuo*

*Department of Medicine, †Charles and Jane Pak Center for Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas

ABSTRACT deficiency is likely associated with en- ϩ is frequently associated with hypokalemia. Concomitant hanced renal K excretion. To support magnesium deficiency aggravates hypokalemia and renders it refractory to treat- this idea, Baehler et al.5 showed that ad- ment by . Herein is reviewed literature suggesting that magnesium ministration of magnesium decreases ϩ deficiency exacerbates potassium wasting by increasing distal potassium secre- urinary K excretion and increases se- ϩ tion. A decrease in intracellular magnesium, caused by magnesium deficiency, rum K levels in a patient with Bartter releases the magnesium-mediated inhibition of ROMK channels and increases disease with combined hypomagnesemia potassium secretion. Magnesium deficiency alone, however, does not necessarily and hypokalemia. Similarly, magnesium ϩ cause hypokalemia. An increase in distal delivery or elevated replacement alone (without K ) in- ϩ levels may be required for exacerbating potassium wasting in magnesium creases serum K levels in individuals deficiency. who have hypokalemia and hypomag- nesemia and receive treatment.6 J Am Soc Nephrol 18: 2649–2652, 2007. doi: 10.1681/ASN.2007070792 Magnesium administration decreased urinary Kϩ excretion in these individuals (Dr. Charles Pak, personal communica- Hypokalemia is among the most fre- cin B, , etc. Concomitant magne- tion, UT Southwestern Medical Center quently encountered fluid and electro- sium deficiency has long been appreci- at Dallas, July 13, 2007). Moreover, mag- lyte abnormalities in clinical medicine. ated to aggravate hypokalemia.2 nesium infusion decreases urinary Kϩ ϩ The concentration of potassium (K )in Hypokalemia associated with magne- excretion in normal individuals.7 the serum is a balance among intake, ex- sium deficiency is often refractory to Kϩ is freely filtered at the glomerulus. ϩ cretion, and distribution between the ex- treatment with K . Co-administration Most of the filtered Kϩ is reabsorbed by tra- and intracellular spaces.1 Accord- of magnesium is essential for correcting the and the loop of ingly, hypokalemia may be caused by the hypokalemia. The mechanism of hy- Henle. Kϩ secretion occurs in the late ϩ redistribution of K from serum to cells, pokalemia in magnesium deficiency, and the cortical decreased dietary intake, or excessive loss however, remains unexplained. Here, we collecting duct, which contributes in ϩ ϩ of K from the gastrointestinal track or review existing literature on the subject large part to urinary K excretion.1 Ka- from the . Understandably, hypo- to provide better understanding of the mel et al.8 addressed the tubular site of kalemia from excess renal or gastrointes- mechanism. Because of space limita- action of magnesium by measuring the tinal loss or reduced intake would likely tions, this review cites review articles in transtubular Kϩ concentration gradient be associated with loss and deficiency of lieu of many original publications. (TTKG). The TTKGprovides an indirect other . It is estimated that more than Previous articles suggested that im- 50% of clinically significant hypokalemia pairment of Na-K-ATPase caused by ϩ has concomitant magnesium deficiency. magnesium deficiency contributes to K Published online ahead of print. Publication date ϩ Clinically, combined K and magne- wasting.3,4 Magnesium deficiency im- available at www.jasn.org. sium deficiency is most frequently ob- pairs Na-K-ATPase, which would de- Correspondence to: Dr. Chou-Long Huang, or Dr. ϩ served in individuals receiving loop or crease cellular uptake of K .3 A decrease Elizabeth ϩ Kuo, UT Southwestern Medical Center, Department 1 thiazide therapy. Other causes in cellular uptake of K , if it occurs along of Medicine, 5323 Harry Hines Boulevard, Dallas, TX include ; ; intrinsic with increased urinary or gastrointesti- 75390-8856. Phone: renal tubular transport disorders such as nal excretion, would lead to Kϩ wasting 214-648-8627;Fax:214-648-2071;E-mail:chou-long. ϩ [email protected]; elizabeth.kuo@ Bartter and Gitelman syndromes; and and hypokalemia. Little K is excreted utsouthwestern.edu tubular injuries from nephrotoxic drugs, by the normally; Copyright © 2007 by the American Society of including aminoglycosides, amphoteri- therefore, hypokalemia in magnesium Nephrology

J Am Soc Nephrol 18: 2649–2652, 2007 ISSN : 1046-6673/1810-2649 2649 SCIENCE IN RENAL MEDICINE www.jasn.org

Influx Efflux Aldosterone A Zero Mg2+ B Zero Mg2+ + Out In Out In Delivery –100 mV –50 mV + + Na ENaC Na K+ K+ + + Depolarize Na Na-K-ATPase + K 5 mM 140 mM 5 mM 140 mM + K ROMK EK = –86 mV EK = –86 mV Blood C 1 mM Mg2+ D 1 mM Mg2+

Mg2+ –100 mV –50 mV

ϩ 2+ Figure 1. K secretion in the distal Mg ϩ nephron. K is taken up into cells across the basolateral membrane via Na-K-AT- 5 mM 140 mM 5 mM 140 mM Pases (blue oval) and secreted into luminal E = –86 mV E = –86 mV fluid via apical ROMK channels (yellow cyl- K K ϩ ϩ inder). Sodium (Na ) reabsorption via Figure 2. Mechanism for intracellular magnesium to decrease K secretion. A ROMK ENaC (green cylinder) depolarizes the api- channel in the apical membrane of distal nephron is depicted. (A and B) At zero cal membrane potential and provides the 2ϩ ϩ ϩ intracellular Mg ,K ions move in or out of cell through ROMK channels freely ϩ driving force for K secretion (indicated by depending on the driving force (i.e., not rectifying). At intra- and extracellular K dotted line and plus sign). Thus, increased ϩ ϩ concentrations of 140 and 5 mM, respectively, the chemical gradient drives K outward. Na delivery (indicated by black line) ϩ ϩ An inside-negative membrane potential drives K inward. Inward and outward move- would stimulate K secretion. Aldosterone ϩ Ϫ ϭϪ ϫ ment of K ions reach an equilibrium at 86 mV (i.e., equilibrium potential [EK] 60 increases sodium reabsorption via ENaC to 140 Ϫ ϩ log ⁄5). When membrane potential is more negative than EK (e.g., 100 mV, a ϩ stimulate K secretion (indicated by red condition that rarely occurs in the apical membrane of distal nephron physiologically), K line). ions move in (influx; see A). Conversely, at membrane potential more positive than EK ϩ (e.g., Ϫ50 mV, a physiologic relevant condition), K ions move out (see B). (C and D) At ϩ ϩ ϩ reflection of K secretion in the distal the physiologic intracellular Mg2 concentration (e.g., 1 mM), ROMK conducts more K ϩ nephron. The authors found that mag- ions inward than outward (i.e., inward rectifying). This is because intracellular Mg2 binds ϩ ϩ ROMK and blocks K efflux (secretion; see D). Influx of K ions displaces intracellular nesium infusion (but not ammonium ϩ ϩ Mg2 , allowing maximal K entry (see C). This unique inward-rectifying property of chloride infusion to correct metabolic al- ϩ ϩ ROMK places K secretion in the distal nephron under the regulation by intracellular kalosis) reduced urinary K excretion ϩ ϩ Mg2 . Note that, though inward conductance is greater than outward, K influx (i.e., and decreased TTKG in four of six pa- reabsorption) does not occur because of membrane potential more positive than EK. tients with Gitelman disease and hypo- kalemia, hypomagnesemia, and meta- ϩ ϩ bolic . Thus, magnesium than out.12 Sodium (Na ) reabsorption logic extracellular K and apical mem- ϩ replacement prevents renal Kϩ wasting, via epithelial Na channel (ENaC) depo- brane potential in the distal nephron, the at least in part, by decreasing secretion in larizes the apical membrane potential, effective intracellular concentration of ϩ ϩ the distal nephron. Previous micropunc- which provides the driving force for K Mg2 for inhibiting ROMK ranges from ture studies also confirmed that magne- secretion. Aldosterone increases sodium 0.1 to 10.0 mM, with the median concen- ϩ ϩ sium decreases distal K secretion.9,10 reabsorption via ENaC to stimulate K tration at approximately 1.0 mM.13 The ϩ What is the cellular mechanism for secretion (Figure 1). Maxi-K channels intracellular Mg2 concentration is esti- ϩ the decrease in Kϩ secretion by magne- are responsible for flow-stimulated K mated at 0.5 to 1.0 mM.14 Thus, intracel- ϩ sium? In the late distal tubular and corti- secretion (data not shown). Inward rec- lular Mg2 is a critical determinant of ϩ cal collecting duct cells, Kϩ is taken up tification of ROMK results when intra- ROMK-mediated K secretion in the ϩ into cells across the basolateral mem- cellular Mg2 binds and blocks the pore distal nephron. Changes in intracellular ϩ brane via Na-K-ATPases and secreted of the channel from the inside, thereby Mg2 concentration over the physiolog- ϩ into luminal fluid via apical Kϩ channels. limiting outward K flux (efflux). In- ic-pathophysiologic range would signifi- ϩ ϩ Two types of Kϩ channels mediate apical ward K flux (influx) would displace in- cantly affect K secretion. ϩ Kϩ secretion: ROMK and maxi-K chan- tracellular Mg2 from the pore and re- Magnesium is the most abundant di- nels. ROMK is an inward-rectifying Kϩ lease the block (Figure 2). The valent cation in the body. Approximately ϩ channel responsible for basal (non–flow concentration of intracellular Mg2 re- 60% of magnesium is stored in , an- ϩ stimulated) K secretion.11 Inward recti- quired for inhibition of ROMK depends other 38% is intracellular in soft tissues, fication means that Kϩ ions flow in the on membrane voltage and the extracellu- and only approximately 2% is in extra- ϩ cells through channels more readily lar concentration of K .13 At the physio- cellular fluid including the plasma. The

2650 Journal of the American Society of Nephrology J Am Soc Nephrol 18: 2649–2652, 2007 www.jasn.org SCIENCE IN RENAL MEDICINE

Outward ROMK ×=Driving Potassium critical for stabilizing membrane poten- conductance force secretion tial and decreasing cell excitability.16 Magnesium replete ++ ++ + Magnesium deficiency will not only ex- acerbate Kϩ wasting but also aggravate Magnesium deficient the adverse effects of hypokalemia on target tissues.16 Recognition of concom- Alone + + + + + itant magnesium deficiency and early + Sodium delivery + + + + + + + + treatment with magnesium are impera- + Aldosterone + + + + + + + + tive for effective treatment and preven- tion of complications of hypokalemia. ϩ Figure 3. Summary of effects of intracellular magnesium and driving force on K secretion. ACKNOWLEDGMENTS cytosol is the largest intracellular com- and urinary Kϩ excretion are normal. How 2ϩ 2ϩ partment for Mg . The cellular Mg do these findings reconcile with the pro- C.-L.H. is supported by grants from the Na- concentration is estimated between 10 to posed model that lowering intracellular tional Institutes of Health (DK54368 and 2ϩ 2ϩ ϩ 20 mM. In the cytosol, Mg ions mainly Mg increases ROMK-mediated K se- DK59530) and the Jacob Lemann Professor- form complexes with ATP and, to a cretion in the distal tubules? One reason ship in Transport at University of smaller extent, with other nucleotides for the lack of significant hypokalemia and Texas Southwestern Medical Center and is an ϩ and enzymes. Only approximately 5% of K wasting in isolated magnesium defi- established investigator of the American 2ϩ Mg (0.5 to 1.0 mM) in the cytosol is ciency is related to the impairment of Na- Association (0440019N). ϩ free (unbound).14 The degree of ex- K-ATPase. Decreased cellular K uptake We thank Drs. Michel Baum, Orson Moe, 2ϩ change of Mg between tissues and in the muscle and the kidney would tend to Charles Pak, and Robert Reilly for critical ϩ plasma varies greatly. It was shown in maintain serum K levels but decrease re- reading and comments on the manuscript. ϩ kidney and heart that 100% of intracel- nal K secretion4,10; therefore, additional lular Mg2ϩ can exchange with plasma factors are needed for promoting renal Kϩ 15 within 3 to 4 h. In contrast, only ap- excretion. Another reason is related to the DISCLOSURES proximately 10% of magnesium in brain fact that ROMK channels in the apical None. and 25% in can exchange membrane of distal tubules also play an with plasma, and the equilibrium occurs important role in regulating membrane ϩ after Ն16 h. The basis for the differences potential.11 An increase in the K secretion REFERENCES is not known. 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