NORMAL POTASSIUM DISTRIBUTION AND BALANCE

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1 NORMAL POTASSIUM DISTRIBUTION AND BALANCE 98% of body potassium is contained within cells, principally muscle cells, and is readily exchangeable. Only 2% is in ECF. Daily intake exceeds the amount in ECF. The plasma [K] is maintained between 3.5 to 5.0 meq/l. The kidney excretes 90-95% of the daily intake. The rest is excreted by the GI tract.

2 BALANCE BETWEEN CELLULAR AND EXTRACELLULAR K Muscles Liver RBCs K K INSULIN EPINEPHRINE ALDOSTERONE - These three hormones stimulate Na-K-ATPase increasing cellular uptake of K from the ECF. Insulin levels are increased by food intake and by a rise in [K ] p by > 1mM. Epinephrine levels are increased by stress. It acts through β receptors. Aldosterone levels are increased by AII and by a rise in [K ] p.

3 EFFECT OF ACID-BASE CHANGES ON K DISTRIBUTION Respiratory changes in acid-base balance have little effect on K distribution between ICF and ECF. Metabolic acidosis produced by the addition of inorganic acids causes K loss from cells. Metabolic alkalosis has the opposite effect. This may be due to impermeant cellular buffers. X - H HX The negatively charged, alkaline form of the buffer balances the cation K. However titration of the buffer to the acid form removes anionic charges within the cell and causes K to leave the cell. Metabolic alkalosis would have the opposite effect. Accumulation of organic acids in the blood (lactic acid, acetic acid, keto acids) have a much smaller effect on K distribution. This may be because the acid form of these compounds can move across the cell membrane to some extent, neither adding or removing H from the cell.

4 EFFECT OF K P ON ACTION POTENTIALS K P K P MILD HYPO- KALEMIA NORMAL Resting membrane potential is proportional to gk x log Ki/Ko HYPERKALEMIA OR SEVERE HYPO- KALEMIA A mild fall in plasma K increases the ratio Ki/Ko, which hyperpolarizes the resting membrane potential, increasing the strength of stimulus required to activate fast Na channels. A rise in plasma K decreases the resting membrane potential, which depolarizes the resting potential and partially inactivates fast Na channels. A severe fall in plasma K leads to a reduction in gk, which depolarizes the resting potential and partially inactivates fast Na channels.

5 TUBULAR TRANSPORT OF POTASSIUM 70-75% of filtered K is reabsorbed in the proximal tubule without a change in tubular fluid concentration. An additional 12-20% is reabsorbed in the loop of Henle and distal tubule. K is secreted by the late distal tubule and collecting tubule. Secretion accounts for almost all of the K that is excreted. Some K reabsorption also occurs in the collecting duct. K reabsorption by the proximal tubule and Henle s loop varies little. K secretion accounts for almost all of the K excreted. Physiological variations in K excretion are due primarily to changes in secretion. 800 meq/day filtered 70-75% reabsorbed 10-15% reabsorbed 2-5% reabsorbed % secreted 6-40% reabsorbed 2-150% excreted

6 K REABSORPTION IN THE PROXIMAL TUBULE K reabsorption In the proximal tubule occurs via the paracellular channels. A small fraction of water reabsorption occurs via that pathway and entraps K in that flow. This is a process called solvent drag. K H2O

7 K REABSORPTION IN THE THICK ASCENDING LIMB K is transported into the cell by the Na-K-2Cl cotransporter in the apical membrane. Some of that K is returned to the tubular fluid but a fraction of it enters the medullary ISF via a K channel in the basolateral membrane. The countercurrent mechanism tends to concentrate K in the medullary interstitium much as it does with Na. 2Cl - K K Cl - - -

8 POTASSIUM SECRETION K is secreted by principal cells in late distal tubule and collecting tubule. K is transported into the cell from the ISF by the Na-K ATPase pump. K enters the tubular fluid via a K channel in the apical membrane. Movement through that channel is driven by the chemical gradient and opposed by the electrical gradient across the apical membrane. Na influx through the ENaC channel reduces the electrical gradient, thereby favoring K exit. - K K K - -

9 FACTORS AFFECTING K SECRETION The following factors in the blood stimulate K secretion. Aldosterone stimulates Na-K ATPase and Na and K channels. ADH stimulates K flow across the apical membrane by increasing Na uptake across the apical membrane [K] p increases K uptake. Alkalosis also increases K uptake. The following factors in tubular fluid also stimulate K secretion. Na reduces electrical gradient across apical membrane V maintains favorable chemical gradient for secretion. gradient across apical membrane ph increases apical gk. Na V ph - ALDOSTERONE ADH [K] p ALKALOSIS K K K - -

10 ADH MAINTAINS POTASSIUM BALANCE Urinary Flow Rate Water Diuresis Distal K Secretion ADH Levels Urinary Flow Rate Constant K Balance Antidiuresis Distal K Secretion ADH Levels

11 EFFECT OF DIURETIC AGENTS Diuretic agents are often prescribed in order to reduce blood pressure and ECF volume by increasing salt and water excretion. Most of these agents have the unwanted side effect of increasing potassium excretion, requiring periodic monitoring of the blood [K] in order to avoid potassium depletion. Most of these agents stimulate K secretion by increasing tubular fluid flow rate and the supply of Na to the collecting tubule. The loop diuretics, furosamide and bumetanide, inhibit the Na-K-2Cl cotransporter in the loop of Henle. This inhibits Na, Cl and K reabsorption there and the reabsorption of water in the collecting tubule. The thiazide diuretics, such as chlorothiazide, inhibit Na, Cl and water reabsorption in the distal tubule. The carbonic anhydrase inhibitors, such as acetazoleamide, depress HCO3, Na and water reabsorption in the proximal tubule, and raise tubular fluid ph which also stimulates K secretion. Amiloride depresses K secretion by blocking the ENaC channel. Spironolactone also depresses K secretion, by blocking the cellular receptor for aldosterone.

12 ASSESSING ACTIVITY OF K SECRETORY PROCESS Calculation of the TTKG, the transtubular potassium concentration gradient in the cortical CD provides an index of activity of the K secretory process. TTKG = (U K /P K ) / (U osm /P osm ) cortex medulla U K /P K is assumed to have been raised by water reabsorption in the medullary CD. Dividing it by U osm /P osm corrects it to the ratio assumed to have existed in the cortical CD. The use of TTKG is restricted to situations in which the urine is not hypotonic and distal nephron sodium delivery is adequate for normal K secretion.

13 USEFULNESS OF TTKG In normal subjects TTKG approximates 8. In presence of Aldosterone and ADH it may equal 10 and might increase to after mineralocorticoid administration or K loading. In K deprivation, TTKG may decline towards one. It can be used to assess whether K wasting is due to extrarenal or renal causes. It is important to remember that K reabsorption occurs in the inner and outer medullary CD and that K secretion may occur in the inner medullary CD.

14 What is man, when you come to think upon him, but a minutely set, ingenious machine for turning, with infinite artfulness, the red wine of Shiraz into urine? Isak Dinesen