Potassium Flashcards
Potassium Physiology and Homeostasis
Potassium Background
Total body K+ stores in adults: ~3,000 to 4,000 mEq (50 to 55 mEq/kg body weight)
Unlike Na+, 98% of K+ is intracellular. Intracellular K+ concentration is ~140 mEq/L whereas plasma K+ is ~4 to 4.5 mEq/L.
Potassium Physiology and Homeostasis
Potassium Background
The differential location of Na+ and K+ is maintained by (3)Na+- (2)K+-ATPase in cell membrane, which pumps 3 Na+ out in exchange for 2 K+ into cell (3:2 ratio).
Functions of K+
Cell metabolism (i.e., regulation of protein and glycogen synthesis)
Major determinant of resting membrane potential across cell membrane → necessary for generation of action potential required for normal neural and muscular function
Plasma K+ concentration (P[K+]), typically measured as serum K+ (S[K+]) and total body content depend on:
Input: blood transfusions (particularly old blood products due to extracellular K+ leakage), dietary supplements (salt substitutes [KCl], high K+-containing foods)
Plasma K+ concentration (P[K+]), typically measured as serum K+ (S[K+]) and total body content depend on:
Output (i.e., bodily loss): skin (sweats, extensive burns), respiratory (airway secretions), gastrointestines (large volume vomiting, nasogastric suctions, fistulas/drainages, diarrhea, renal excretion)
Plasma K+ concentration (P[K+]), typically measured as serum K+ (S[K+]) and total body content depend on:
Cellular K+ Shifts:
Major Determinants
Plasma K+ concentration (P[K+]), typically measured as serum K+ (S[K+]) and total body content depend on:
Cellular K+ Shifts:
Major Determinants
K+ loss associated with GI fluid loss occurs via:
Direct K+ loss from vomitus/gastric fluids is relatively low—~5 to 20 mEq/L of fluid loss.
More significantly, there is renal K+ loss via associated volume depletion, compensatory hyperrenin, and hyperaldosteronism.
Plasma K+ concentration (P[K+]), typically measured as serum K+ (S[K+]) and total body content depend on:
Cellular K+ Shifts:
Major Determinants
Extracellular pH:
Low extracellular pH shifts K+ out of cells in exchange for H+ and vice versa (K+/H+exchange).
This effect is most pronounced with kidney failure–associated metabolic acidosis and less pronounced with organic acidoses (lactic acid, ketoacids), metabolic alkalosis, and respiratory acidosis/alkalosis.
Plasma K+ concentration (P[K+]), typically measured as serum K+ (S[K+]) and total body content depend on:
Cellular K+ Shifts:
Major Determinants
Extracellular osmolality: Hyperosmolality shifts water out of cells, which leads to:
Higher intracellular K+ concentration, hence more favorable gradient for K+ exit into plasma
Extracellular K+ shift due to solvent drag effect
Plasma K+ concentration (P[K+]), typically measured as serum K+ (S[K+]) and total body content depend on:
Cellular K+ Shifts:
Major Determinants
Na+-K+-ATPase:
Stimulated by insulin, aldosterone, β2-agonists (e.g., drug-induced cellular K+ uptake, thus hypokalemia: albuterol, terbutaline, dobutamine, isoproterenol)
Plasma K+ concentration (P[K+]), typically measured as serum K+ (S[K+]) and total body content depend on:
Cellular K+ Shifts:
Major Determinants
Na+-K+-ATPase:
Inhibited by α-agonists, presumably via inhibition of renin release, thus downstream hypoaldosteronism and hyperkalemia. (NOTE: α-agonists are vasoconstrictive agents such as phenylephrine and the commonly used agent norepinephrine in the critical care setting. These agents may cause hyperkalemia via their α-agonistic activity). Dopamine has weak to moderate α-1 activity and could contribute to minimal increase in S[K+] if used in high doses.
Plasma K+ concentration (P[K+]), typically measured as serum K+ (S[K+]) and total body content depend on:
Cellular K+ Shifts:
Major Determinants
ATP-dependent K+ channels: ATP depletion with exercise opens up more K+ channels →K+ leaves cells → local increase in plasma K+ enhances vasodilatation, hence blood flow and energy delivery to exercising muscles. This effect is impaired with K+ depletion.
Plasma K+ concentration (P[K+]), typically measured as serum K+ (S[K+]) and total body content depend on:
Cellular K+ Shifts:
Major Determinants
Plasma K+ concentration: Passive movement in or out of cells depends on acute plasma K+concentration changes.
Cell lysis: Cellular K+ release into plasma: tumor lysis, rhabdomyolysis, hemolysis, bowel infarction
Plasma K+ concentration (P[K+]), typically measured as serum K+ (S[K+]) and total body content depend on:
Cellular K+ Shifts:
Major Determinants
Cell production/anabolism: K+ uptake for cell production (i.e., red blood cells, platelets) with folic acid or vitamin B12 therapy for megaloblastic anemia; refeeding syndrome.
Renal Potassium Handling:
Potassium balance depends on K+ Reabsorption and Secretion
K+-reabsorption:
Proximal tubules: passive reabsorption; follows Na+ reabsorption
Thick ascending limb loop of Henle: active reabsorption via Na+-K+-2Cl
K+-reabsorption:
Cortical and outer medullary collecting ducts α-intercalated cells H+-K+-ATPase reabsorbs K+ in exchange for H+; Activity of this pump is increased with K+ depletion and reduced with K+loading and facilitated by aldosterone.
K+ secretion:
Medullary K+ recycling:
Reabsorbed medullary K+ is secreted back into the lumen at the S3 segment of late proximal tubules and descending limb loop of Henle for subsequent reabsorption at thick ascending limb loop of Henle.
Maintenance of high medullary K+ concentration is thought to minimize passive K+ back-leak
Regulated K+ secretion via the renal outer medullary potassium channel (ROMK) at the connecting and collecting tubules:
Efficiency depends on plasma K+ concentration and (1) distal Na+ delivery, (2) generation of transepithelial potential difference (negative lumen) via Na+ entry into ENaC in principal cells at aldosterone-sensitive distal nephron segment, (3) distal urine flow (to maintain the favorable electrochemical gradient for K+ secretion), (4) presence of aldosterone (regulates expression of ENaC, Na+-K+-ATPase), (5) sensitivity to aldosterone, and (6) kidney mass.
Regulated K+ secretion via the renal outer medullary potassium channel (ROMK) at the connecting and collecting tubules:
ADH is also thought to increase the number of luminal ROMK channels.
NOTE
The first response to a K+ load is intracellular uptake, a process facilitated by basal levels of catecholamines and insulin. Subsequently, the kidneys will excrete any excess K+.
Diagnosis of Potassium Disorders (Dyskalemias)
Common indices used to determine renal versus extrarenal causes of potassium disorders:
Renal Potassium Handling with Normal Renal Function
Long-term potassium homeostasis occurs primarily through changes in renal potassium excretion. Serum potassium is almost completely ionized, is not bound to plasma proteins, and is filtered efficiently by the glomerulus.
The proximal tubule reabsorbs the majority (~65% to 70%) of filtered potassium, but there is relatively little variation in proximal tubule potassium reabsorption in response to hypokalemia or hyperkalemia.
In the loop of Henle, potassium is secreted in the descending loop, at least in deep nephrons, particularly with adaptation to a large K+ intake, and is reabsorbed in the ascending loop through the action of the Na+-K+-2Cl− cotransporter.
The collecting duct is the primary site at which the kidney regulates urinary K+ excretion. The collecting duct has the ability both to secrete K+, enabling adaptation to K+ excess states, and to actively reabsorb K+, enabling adaptation to K+ depletion states.
The principal cell, particularly in the cortical collecting duct, secretes potassium, whereas intercalated cells throughout the entire collecting duct reabsorb potassium. In the principal cell, sodium is reabsorbed through the apical epithelial sodium channel (ENaC), which stimulates basolateral Na+,K+-ATPase; active potassium uptake by this protein maintains a high intracellular K+.
Subsequent to basolateral potassium uptake, K+ is secreted across the apical plasma membrane of principal cells into the luminal fluid by apical potassium channels and KCl cotransporters. Intercalated cells, in contrast, actively reabsorb potassium through an apical H+-K+-ATPase6; this protein actively secretes H+ into the luminal fluid in exchange for reabsorption of luminal potassium.
The presence of two separate potassium transport processes, secretion by principal cells and reabsorption by intercalated cells, contributes to rapid and effective regulation of renal potassium excretion.
Several factors influence principal cell potassium secretion. In relative order of importance these include luminal flow rate, distal sodium delivery, aldosterone, extracellular potassium intake, and extracellular pH. Under conditions in which Na+delivery or luminal [Na+] is drastically reduced, K+ excretion falls precipitously due to decreased K+ secretion.
An increase in luminal flow rate reduces changes in luminal [K+] that would otherwise result from K+secretion, thereby minimizing changes in the concentration gradient across the apical membrane and facilitating continued K+ transport. In addition, flow rate directly influences cellular potassium secretion by modulating the activity of potassium channels.
Reduced luminal flow, such as occurs in pre-renal azotemia and obstruction, may contribute to the hyperkalemia that is often seen in these conditions. Decreased sodium reabsorption, whether from reduced luminal sodium delivery or treatment with sodium channel inhibitors, i.e., potassium-sparing diuretics, decreases K+secretion by altering electrochemical forces for K+ secretion.
Conversely, increased sodium delivery to the collecting duct, as may occur with either a high-salt diet or administration of either loop or thiazide diuretics, increases principal cell sodium reabsorption and causes a secondary increase in potassium secretion.
Aldosterone has many effects that increase principal cell potassium secretion, including increased Na+,K+-ATPase, increased apical expression of ENaC, and increased apical K+ channels. The net effect is increased principal cell-mediated K+ secretion.
Changes in extracellular potassium directly alter Na+,K+-ATPase activity, thereby altering increased K+ secretion. Metabolic acidosis decreases K+ secretion, both through direct effects on potassium channels and through changes in interstitial ammonia concentration, both of which decrease K+ secretion.7 Respiratory acidosis has minimal effect on K+ secretion, whereas acute respiratory alkalosis can cause marked increases in K+ excretion associated with increases in urinary bicarbonate excretion.
Intercalated cell-mediated potassium reabsorption occurs in parallel with principal cell-mediated potassium secretion. Active potassium reabsorption occurs through the action of the potassium-reabsorbing protein, H+-K+-ATPase. The major factors regulating H+-K+-ATPase expression and activity include potassium balance, aldosterone, and acid-base status.
Potassium depletion increases H+-K+-ATPase expression, resulting in increased active potassium reabsorption and decreased net potassium excretion. Aldosterone increases H+-K+-ATPase expression and activity and, by decreasing net potassium excretion, may minimize changes in urinary potassium excretion during aldosterone excess that otherwise would lead to more severe hypokalemia. Metabolic acidosis has both direct and indirect effects, mediated through alterations in ammonia metabolism, that increase H+-K+-ATPase potassium reabsorption.
Fundamental regulators of renal K+ transport in the distal nephron include the “with no lysine” or “WNK” kinases. WNK kinases activate Na+ reabsorption in the distal convoluted tubule as well as inhibiting the renal outer medulla potassium (ROMK) channel. This combination of effects, increased DCT Na+ reabsorption, which decreases collecting duct Na+ delivery, in conjunction with decreased ROMK expression, promotes decreased K+ secretion.
Extracellular K alters intracellular Cl− through direct effects on membrane voltage; the former appears to directly regulates WNK activity. This results in hypokalemia activating and hyperkalemia inhibiting WNK activity. Medications targeting WNK inhibition are in development and may in the future enable entirely new treatments of hypertension and K+ disorders.
Renal Potassium Handling in Chronic Kidney Disease
Because the kidneys are the major route for elimination of potassium, as renal function declines the balance among dietary potassium intake, renal potassium excretion, and baseline serum potassium changes. In general, most patients with chronic kidney disease (CKD) are able to maintain their serum potassium in the normal range, although there is a graded increase in mean serum K+ as the glomerular filtration rate (GFR) declines.
The risk for developing hyperkalemia is increased in patients with stage IV CKD; patients with stage III CKD who have diabetes mellitus, tubulointerstitial disease, or receive certain drugs also are at increased risk.
Many of the medications used in the treatment of patients with CKD have important effects on potassium homeostasis. Common medications that predispose to hyperkalemia include agents that inhibit the ENaC or renin-angiotensin-aldosterone system (RAAS), nonsteroidal antiinflammatory drugs (NSAIDs), and calcineurin inhibitors. Medications that can directly inhibit ENaC, such as amiloride, triamterene, trimethoprim, and pentamidine, may acutely reduce the rate of renal K+excretion and cause hyperkalemia.
Drugs that inhibit the RAAS, such as mineralocorticoid receptor (MR) blockers, angiotensin receptor blockers (ARBs), angiotensin-converting enzyme (ACE) inhibitors, direct renin inhibitors, and heparin, have the potential to inhibit the action of aldosterone, which reduces renal clearance of K+.
Mineralocorticoid blockers are increasingly used in patients with congestive heart failure and refractory hypertension and have potential benefit to slow the progression of CKD. NSAIDs that inhibit prostaglandin synthesis and β-blockers that inhibit renin release and catecholamine action also can increase the risk for hyperkalemia. In contrast, both loop and thiazide diuretics increase renal K+ excretion and predispose to hypokalemia.
