mechanism of hypokalemia in magnesium deficiency

Mechanism of hypokalemiain magnesium deficiency~JASN2007

Editor:T.K.

Overview

• Foreword• Hypokalemia• Concomitant hypoK+ and Mg2+ deficiency• Mechanism of hypoK+ in Mg2+ deficiency • HypoMg2+ without hypoK+

• Summary

Foreword

• Hypokalemia is among the most frequent electrolyte imbalance and frequetlyassociated by magnesium deficiency.

• Concomitant magnesium deficiency aggravates hypokalemia and renders it refractory to treatment by potassium alone.

Hypokalemia

Definition• Definition: plasma K < 3.5 mEq/LEtiology• Decreased intake• Shift into cells• Increased loss

*> 50% hypoK+ accompany with Mg2+

deficiency

Concomitant hypoK+ and Mg2+

deficiency• Use loop or thiazide diuretic • Diarrhea• Alcoholism• Bartter’s and Gitelman’s syndrome• Tubular injury from nephrotoxic drugs,

including aminoglycosides, amp B, cisplatin,etc

Mechanism of Mechanism of hypoK+ in Mg2+ deficiency (1)

Old concept • Na-K-ATPase channel dysfunction by hypoMg2+

*Baehler RW,et al.Studies on thepathogenesis of Bartter’s syndrom. AJM 1980

Ruml, et al.Effect of potassium magnesium citrate on thiazide-induced hypokalemia and magesium loss. AJKD 1999

Heller Bl, et al.Concerning the effects of magnesium sulfate on renal function,electrolyte excretion, and clearance of magnesium. JCI 1953

Kamel SK, et al.Studies on the pathogenesis of hypokalemia in Gitelman’ssyndrome. AJN 1998

Mechanism of Mechanism of hypoK+ in Mg2+ deficiency(2)

K+ metabolism • Freely filtered at the glomerulus• Most reabsorb by proximal convoluted

tubule(PCT) and the loop of Henle• Secretion at distal convoluted tubule(DCT)

and cortical collecting duct(CCD)

Mechanism of Mechanism of hypoK+ in Mg2+ deficiency(3)

K+ at DCT and CCT• K+ taken up via basolateral Na-K-ATPase• K+ secreted via apical K+ channels

ROMK channelMaxi-K(BK) channel

• ROMK is an inward-rectifying(inward-prone) K+ channel

Figure 1. K+ secretion in the distal nephron

Huang, C.-L. et al. J Am Soc Nephrol 2007;18:2649-2652

Copyright ©2007 American Society of Nephrology

Mechanism of Mechanism of hypoK+ in Mg2+ deficiency(4)

ROMK as an inward rectifying K+ channel• Intracellular Mg2+ binds and blocks the pore

of the channel from the inside• Limit K+ efflux from the cell• NOT limit K+ influx into the cell

Figure 2. Mechanism for intracellular magnesium to decrease K+ secretion

Huang, C.-L. et al. J Am Soc Nephrol 2007;18:2649-2652

Copyright ©2007 American Society of Nephrology

Mechanism of Mechanism of hypoK+ in Mg2+ deficiency(5)

How much Mg2+ is sufficient for ROMK to inhibition• Median effective intracellular Mg2+ concentration

for ROMK inhibition: 1.0 mM* determined by membrane voltage and

extracellular concentration of K+

• Estimated intracellular Mg2+

concentration :0.5~1.0 mM

Mechanism of Mechanism of hypoK+ in Mg2+ deficiency(6)

Physiology of Mg2+ (1)-disturbution• Bone: 60%• Intracellular: 38%

10~20mM, mainly in cytosol bind with ATP5% free(0.5~1.0mM)

• Extracellular: 2%

Mechanism of Mechanism of hypoK+ in Mg2+ deficiency(7)

Physiology of Mg2+ (2)- intra-extra cell shift• Heart and kidney: 100% in 3~4h• Brain: 10%, >16hr• Skeletal muscle: 25%, >16hr

HypoMg2+ without hypoK+ (1)

Genetic disorders of isolated hypoMg2+ (w/o hypoK) • Familial hypomagnesemia with hypercalciuria

and nephrocalcinosis(FHHNC)• Hypomagnesemia with secondary hypocalcemiaSerum K+ and urinary K+ excretion are normal

HypoMg2+ without hypoK+ (2)

Proposed reasons for isolated hypoMg2+

• K+ efflux decrease further K+ efflux• Additional factor needed for K+ excretion

increase in distal Na+ deliveryelevated aldosterone levels

Figure 1. K+ secretion in the distal nephron

Huang, C.-L. et al. J Am Soc Nephrol 2007;18:2649-2652

Copyright ©2007 American Society of Nephrology

Figure 3. Summary of effects of intracellular magnesium and driving force on K+ secretion

Huang, C.-L. et al. J Am Soc Nephrol 2007;18:2649-2652

Copyright ©2007 American Society of Nephrology

Summary

• Hypokalemia is common• Concourrent hypokalemia and magnesium

deficiency is common• Magnesium deficiency make hypokalemia

refractory to administration of potassium alone and aggravate adverse effect of hypokalemia on target tissues

• Recognize and treat magnesium deficiency accompany with hypokalemia is important