Kidneys Inc.

medicine and nephrology updates and interesting cases by a practicing nephrologist in USA

Mechanism of hypokalemia in magnesium deficiency

http://jasn.asnjournals.org/cgi/reprint/18/10/2649

I had summarized this article a while ago (before I started blogging) thought it was worthwhile to publish it, both for my benefit as for others.

Hypokalemia is the most common electrolyte disturbance that nephrologists frequently encounter.

Serum potassium (K) depends on intake, excretion & distribution between extra & intracellular spaces

50% of clinically significant hypokalemia has co-existing Mg deficiency and is refractory to treatment unless Mg is corrected. Causes include loop diuretics, thiazide therapy, diarrhea, alcoholism, barter & gitelman’s syndromes, nephrotoxic meds like aminoglycosides, amphotericin, cisplatin

MECHANISMS

Mg deficiency causes impairment of Na K ATPase. This decreases cellular uptake of K. {my interpretation: Since Na K ATPase is present in virtually all cells, serum K should rise. This in turn may send signals to the kidney to get rid of K}. Thus, increased gastrointestinal or urinary losses causes K wasting leading to a decrease in total body potassium. Since GI loss is negligible, kidneys play a vital role in this.

EVIDENCE supporting this :

Urinary K excretion is decreased and serum K increases when Magnesium(Mg) when given to hypokalemic hypomagnesemic patients (Bartter’s syndrome, patients on thiazide diuretics) and

even in normal pts, urinary excretion is decreased with Mg infusion

In patients with Gitelman’s syndrome (hypokalemia, hypomagnesemia & met alkalosis) Transtubular potassium gradient (TTKG) is decreased with Mg infusion

PHYSIOLOGY:

K is freely filtered at glomerulus. Most of it is reabsorbed in the proximal tubule and loop of henle. Some K is then secreted in the late distal convoluted tubule (DCT) & cortical collecting duct (CCD)

CELLULAR MECHANISM:

In late DCT & CCD cells K uptake is at the basolateral membrane (Na K ATPase present only there) then secretion is at the apical side where two types of channels are present. Renal Outer Medullary Potassium (ROMK) & Maxi K channels.

ROMK is inward rectifying K channel responsible for basal K secretion Inward rectifying means “K ions flow into the cells through ion channels more readily than out” I did not understand what this means. I think it may mean that the ROMK channel allows two-way traffic for K but cell-bound direction has two lanes!! That makes it easy for K to move in than move out.

The apical side also has Epithelial Sodium channel (ENaC) that reabsorbs Na & causes depolarization of the apical membrane- this is the driving force for K secretion. This implies whatever increases ENaC activity will also increase K secretion. ( ^ aldosterone)

Inward rectification happens when intracellular Mg binds to & blocks the intracellular end of the ROMK channel

This process in turn is dependent on membrane voltage (depends on Na influx as mentioned before), extra cellular K concentration.

At physiological conditions Mg concentration needed for this is 0.1 -10 mmoles (median 1 mol). Since only 2% of total body Mg is in extracellular fluid, intracellular conc is 10-20 mmols, mainly bound to ATP. Only 5% is free

In kidneys & heart 100% of Mg can equilibrate with the plasma in 3-4 hrs, but for brain it is 10%, muscle 25% Moreover it occurs over 16 hrs.

What this means is that when plasma Mg falls for any reason, the intracellular levels drop first in kidneys & heart. This damages the inward rectifying nature of the ROMK channel

In patients with isolated Mg deficiency, hypokalemia not seen why? Two reasons

1. Because the Na K ATPase is also impaired, this causes less Na uptake by muscle & kidney that will cause K to rise again & become normal..?

{ Doesn’t this also stimulate aldosterone secretion which in turn activates the ENaC in the DCT & CCD?}

2. Increase in K secretion (caused by Mg deficiency as not enough Mg is around to bind to intracellular side of ROMK) causes hyperpolarization of cells in DCT & CCD driving force for outward K flux is decreased and K secretion is limited.

Hypomagnesemia alone is not enough to cause hypokalemia

Additional factors needed are increased sodium delivery & elevated aldosterone levels.

But these factors can independently cause hypokalemia. So How much does hypomagnesemia contribute? Are we back to square one?

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