Medical School · Year 2 · Renal · includes a quiz and discussion video

Lecture 6: Potassium Homeostasis

Unit 2.1: Renal System

Learning Objectives

By the end of this lecture, students will be able to:

1. Describe the distribution and physiologic importance of potassium
2. Explain internal potassium balance (transcellular shifts)
3. Describe external potassium balance (renal handling)
4. Explain the pathophysiology and causes of hypokalemia
5. Explain the pathophysiology and causes of hyperkalemia
6. Apply potassium homeostasis concepts to clinical management

Potassium Distribution and Physiologic Importance

Potassium is the most abundant intracellular cation, with a distribution dramatically different from sodium. Of the approximately 3500 mEq of potassium in a 70-kilogram adult, fully 98 percent resides within cells at concentrations of 140 to 150 mEq/L. The remaining 2 percent is extracellular, where the normal plasma concentration ranges narrowly from 3.5 to 5.0 mEq/L. This steep concentration gradient across cell membranes is essential for cellular function.

The sodium-potassium ATPase maintains this asymmetric distribution by actively pumping potassium into cells and sodium out. This pump extrudes three sodium ions while importing two potassium ions with each ATP molecule consumed, a process accounting for 20 to 40 percent of cellular energy expenditure at rest. The resulting gradient is not merely a passive consequence of cellular metabolism but is actively defended as a physiological necessity.

The potassium gradient is the primary determinant of the resting membrane potential, which approximates -90 mV in most excitable cells. The Nernst equation predicts that membrane potential should equal the equilibrium potential for potassium, with small modifications from other ion conductances. Because excitability depends on the relationship between resting potential and threshold, changes in extracellular potassium concentration profoundly affect cardiac, neural, and muscular function. Hypokalemia makes the resting potential more negative (hyperpolarized), requiring greater stimulation to reach threshold and reducing excitability. Hyperkalemia makes the resting potential less negative (depolarized), initially increasing excitability but ultimately inactivating sodium channels and reducing excitability. Both extremes predispose to arrhythmias and weakness.

Beyond membrane potential, potassium serves as a cofactor for enzymes involved in protein synthesis and glycogen synthesis, and contributes to intracellular osmolality, helping regulate cell volume.

<image>Panel A: Cell diagram showing intracellular space (98%, 140-150 mEq/L) in dark blue and extracellular space (2%, 3.5-5.0 mEq/L) in light blue with Na+/K+-ATPase pumping 3 Na+ out and 2 K+ in with ATP consumption. Panel B: Membrane voltage scale from -90 mV to +30 mV showing normal RMP at -90 mV near threshold. Panel C: Hypokalemia showing hyperpolarized RMP requiring more stimulus to reach threshold; hyperkalemia showing depolarized RMP with partially inactivated sodium channels. Panel D: Note about cardiac arrhythmia risk at both extremes of potassium levels.</image>

Internal Potassium Balance

Internal potassium balance refers to the distribution of potassium between intracellular and extracellular compartments. Shifts across cell membranes can rapidly change plasma potassium concentration without altering total body potassium. Understanding these shifts is essential for interpreting potassium levels and predicting the effects of various clinical conditions and treatments.

Several factors promote potassium entry into cells, lowering plasma concentration. Insulin stimulates the sodium-potassium ATPase, driving potassium uptake independent of its effects on glucose. This action serves as a physiological buffer: dietary potassium absorbed with meals triggers insulin release that facilitates cellular uptake, preventing dangerous postprandial hyperkalemia. Beta-2 adrenergic agonists similarly stimulate the pump through cAMP-mediated phosphorylation, explaining why beta-agonists like albuterol lower potassium levels. Alkalosis promotes potassium entry as hydrogen ions exit cells to buffer the extracellular alkalosis; electroneutrality is maintained by potassium entry.

Conversely, other factors shift potassium out of cells, raising plasma concentration. Insulin deficiency or resistance reduces pump activity, contributing to the hyperkalemia seen in diabetic ketoacidosis. Beta-blockers prevent adrenergically mediated potassium uptake. Acidosis, particularly from mineral acids like hydrochloric acid, causes hydrogen ions to enter cells and potassium to exit; traditionally quoted as a 0.6 mEq/L rise in potassium for each 0.1 unit fall in pH, though the actual relationship varies. Cell lysis from any cause releases intracellular potassium contents directly. Hyperosmolality causes water to leave cells, and solvent drag carries potassium along. Vigorous exercise releases potassium from contracting muscles.

The distinction between mineral and organic acidosis deserves emphasis. Mineral acidosis (from HCl, for example) produces reliable hyperkalemia through the hydrogen-potassium exchange mechanism. Organic acidosis from lactic acid or ketoacids produces less predictable potassium shifts because the organic anions enter cells with hydrogen ions, reducing the driving force for potassium exit. Moreover, in diabetic ketoacidosis, the concurrent insulin deficiency contributes more to hyperkalemia than the acidosis itself.

<image>Panel A: Central cell with factors shifting K+ into cells (lowering plasma K+): insulin stimulating Na+/K+-ATPase, beta-2 agonists via cAMP pathway, alkalosis with H+ leaving/K+ entering shown in blue. Panel B: Factors shifting K+ out of cells (raising plasma K+): insulin deficiency, beta-blockers, mineral acidosis with H+ entering/K+ leaving, cell lysis, hyperosmolality, exercise shown in red. Panel C: Clinical DKA scenario showing patient presenting with normal or high K+ despite total body depletion; treatment with insulin causing rapid K+ drop. Panel D: DKA management note to monitor closely and replace potassium early with opposing color schemes for entry/exit.</image>

External Potassium Balance: Renal Handling

External potassium balance refers to the regulation of total body potassium, accomplished primarily through renal excretion matched to dietary intake. The typical Western diet provides 70 to 100 mEq of potassium daily, and the kidneys adjust excretion to match, maintaining balance.

The kidneys filter approximately 800 mEq of potassium daily, of which 90 percent is reabsorbed and only about 90 to 100 mEq is excreted in the final urine. This net picture, however, obscures the bidirectional handling along the nephron.

The proximal tubule reabsorbs 65 to 70 percent of filtered potassium, primarily through passive paracellular transport driven by solvent drag as water is reabsorbed. This reabsorption is relatively fixed and not subject to physiological regulation.

The thick ascending limb reabsorbs an additional 25 percent of filtered potassium. Potassium enters cells via the apical NKCC2 cotransporter along with sodium and chloride. However, luminal potassium is limiting for NKCC2 activity, so potassium recycled back to the lumen through ROMK channels allows continued NKCC2 function. This recirculation is essential for sodium chloride reabsorption and contributes to the lumen-positive potential that drives paracellular cation reabsorption.

The collecting duct is the principal site of regulated potassium handling, where net secretion or reabsorption can be adjusted according to body needs. Principal cells secrete potassium through ROMK channels into the lumen, while type A intercalated cells can reabsorb potassium through apical H+/K+-ATPase during potassium depletion. Under normal dietary potassium intake, net secretion predominates.

<image>Panel A: Nephron showing glomerulus (100% filtered, ~800 mEq/day) and proximal tubule (65-70% reabsorbed, passive paracellular following water). Panel B: Thick ascending limb (25% reabsorbed via NKCC2 with K+ recycling through ROMK to maintain NKCC2 activity). Panel C: Collecting duct showing principal cells with basolateral Na+/K+-ATPase and apical ROMK for secretion; type A intercalated cells with apical H+/K+-ATPase for reabsorption in depletion. Panel D: Variable collecting duct output with net secretion normally versus net reabsorption in depletion; final output ~90-100 mEq/day matching intake.</image>

Potassium Secretion in the Collecting Duct

The collecting duct principal cell is the key effector of potassium homeostasis, adjusting secretion rates over a wide range to match excretion to intake. Understanding the determinants of secretion explains why various clinical conditions alter potassium levels.

The mechanism of principal cell potassium secretion involves three key transporters. The basolateral sodium-potassium ATPase actively pumps potassium into the cell, establishing high intracellular potassium concentration. The apical epithelial sodium channel ENaC allows sodium to enter the cell, creating a lumen-negative transepithelial potential. The apical ROMK channel provides the pathway for potassium secretion, driven both by the favorable potassium concentration gradient (high inside, low in lumen) and the electrical gradient (lumen negative). The more sodium that enters through ENaC, the more negative the lumen becomes, and the greater the driving force for potassium exit.

Multiple factors determine the rate of potassium secretion. Aldosterone increases secretion by upregulating ENaC, ROMK, and the sodium-potassium ATPase, amplifying all three components. High dietary potassium intake directly stimulates aldosterone release and independently increases ROMK expression. High tubular flow rate maintains a low luminal potassium concentration, preserving the secretory gradient; this explains why loop and thiazide diuretics cause hypokalemia despite not directly affecting the collecting duct. High sodium delivery to the collecting duct provides more sodium for ENaC-mediated entry and thus greater electrical driving force. Alkalosis increases secretion because intracellular pH affects potassium distribution within cells. Acidosis reduces secretion through the opposite mechanism.

The aldosterone paradox describes the observation that aldosterone can produce different effects depending on the stimulus. In volume depletion, aldosterone increases yet potassium excretion may not increase substantially because low sodium delivery to the collecting duct limits ENaC-mediated sodium reabsorption and thus limits the electrical gradient for potassium secretion. In hyperkalemia, aldosterone increases and potassium secretion increases appropriately because sodium delivery is not limiting.

High-conductance BK (maxi-K) channels provide an additional pathway for potassium secretion activated by high flow rates, explaining the flow-dependent component of kaliuresis.

<image>Panel A: Collecting duct principal cell showing basolateral Na+/K+-ATPase pumping 2 K+ in and 3 Na+ out establishing high intracellular K+, and apical ENaC allowing Na+ entry creating lumen-negative potential (-40 mV). Panel B: Apical ROMK allowing K+ to exit down concentration and electrical gradients. Panel C: Determinants of secretion showing aldosterone (increases ENaC, ROMK, Na+/K+-ATPase), high K+ intake, high flow (maintains gradient, activates BK channels), high Na+ delivery, alkalosis increases secretion, acidosis decreases secretion. Panel D: Note about aldosterone paradox explaining different effects depending on stimulus.</image>

Hypokalemia: Causes and Classification

Hypokalemia, defined as serum potassium below 3.5 mEq/L, is classified by severity: mild (3.0-3.4 mEq/L), moderate (2.5-2.9 mEq/L), and severe (below 2.5 mEq/L). This common electrolyte abnormality arises through three general mechanisms.

Transcellular shift moves potassium into cells without changing total body content. Insulin administration is a common cause, particularly when given without potassium supplementation in diabetic ketoacidosis or hyperglycemic states. Beta-2 agonists used for asthma can lower potassium significantly. Alkalosis from any cause shifts potassium intracellularly. Hypokalemic periodic paralysis, caused by mutations in ion channels, produces sudden dramatic shifts with paralytic episodes.

Decreased intake rarely causes hypokalemia alone because the kidney can reduce excretion to as low as 5 to 25 mEq/day. However, poor intake combined with even modest losses can produce deficiency. Prolonged intravenous fluid administration without potassium, anorexia, and alcoholism are common clinical settings.

Increased losses account for most clinically significant hypokalemia and can be gastrointestinal, renal, or cutaneous. Gastrointestinal losses from diarrhea represent direct potassium loss in stool. Vomiting causes hypokalemia primarily through an indirect mechanism: the metabolic alkalosis and volume depletion from vomiting stimulate renal potassium wasting, while the direct gastric loss of potassium is relatively small. Laxative abuse is an underrecognized cause. Renal losses occur with diuretics (loop and thiazide), primary or secondary hyperaldosteronism, renal tubular acidosis types 1 and 2, and magnesium depletion. Bartter syndrome and Gitelman syndrome are inherited tubulopathies that mimic diuretic effects. Excessive sweating can cause potassium depletion, particularly in athletes.

<image>Panel A: Transcellular shift showing cell with K+ moving in, listing insulin, beta-2 agonists, alkalosis, hypokalemic periodic paralysis. Panel B: Decreased intake showing dietary sources with slash marks noting rarely sole cause but contributes (anorexia, alcoholism, prolonged K+-free IV fluids). Panel C: Increased losses subdivided into GI (diarrhea direct loss, vomiting indirect renal mechanism), renal (diuretics, hyperaldosteronism, RTAs, hypomagnesemia, Bartter/Gitelman), cutaneous (excessive sweating). Panel D: Diagnostic arrow showing urine K+ measurement with less than 20 mEq/day indicating extrarenal and greater than 20 mEq/day indicating renal losses.</image>

Hypokalemia: Clinical Features and Treatment

The clinical manifestations of hypokalemia reflect the importance of potassium for neuromuscular and cardiac function. Muscular effects include weakness, which may progress to frank paralysis with severe depletion. Cramps are common. In extreme cases, rhabdomyolysis can occur. Smooth muscle is also affected, producing constipation and potentially ileus.

Cardiac effects are particularly concerning. Hypokalemia predisposes to arrhythmias including premature atrial and ventricular contractions, atrial fibrillation, and potentially lethal ventricular tachycardia or fibrillation. The risk is markedly increased in patients taking digoxin because hypokalemia enhances digoxin toxicity by increasing its binding to the sodium-potassium ATPase.

The ECG shows characteristic changes that progress with worsening hypokalemia. Early findings include flattening of the T wave and ST segment depression. The pathognomonic finding is the U wave, a small positive deflection following the T wave, best seen in the precordial leads. As hypokalemia worsens, the U wave may merge with the T wave, creating apparent QT prolongation. Eventually, arrhythmias emerge.

Renal effects of chronic hypokalemia include impaired concentrating ability manifesting as polyuria (a form of acquired nephrogenic diabetes insipidus) and increased ammonia production that may precipitate hepatic encephalopathy in patients with liver disease.

Metabolic alkalosis both causes and is caused by hypokalemia in a reinforcing cycle. Hypokalemia promotes renal acid excretion, generating alkalosis. Alkalosis promotes potassium secretion, worsening hypokalemia.

Treatment replaces potassium while addressing the underlying cause. Oral replacement is preferred for mild to moderate asymptomatic hypokalemia, typically 40 to 80 mEq daily in divided doses. Potassium chloride is the standard preparation, also correcting the chloride depletion that often accompanies hypokalemia. For severe hypokalemia or symptomatic patients unable to take oral replacement, intravenous potassium is necessary but must be given carefully: peripheral infusion should not exceed 10 to 20 mEq per hour, while central venous administration with continuous cardiac monitoring allows up to 40 mEq per hour in emergencies.

A critical point in hypokalemia management: if hypomagnesemia coexists, potassium repletion will fail until magnesium is corrected. Magnesium depletion increases renal potassium wasting and must be addressed for potassium levels to normalize.

<image>Panel A: ECG strip with labeled progression showing T wave flattening, ST depression, U wave appearance with arrow, U-T wave fusion, and arrhythmias with normal comparison. Panel B: Clinical manifestations by organ system: cardiac (arrhythmias, digoxin sensitivity), muscular (weakness, paralysis, rhabdomyolysis), GI (constipation, ileus), renal (polyuria, concentrating defect). Panel C: Treatment algorithm showing severity assessment, oral versus IV route selection, specific dosing (oral 40-80 mEq/day, IV 20 mEq/hr peripheral, 40 mEq/hr central with monitoring). Panel D: Prominent reminder box to check and correct magnesium first as refractory if Mg2+ low.</image>

Hyperkalemia: Causes and Classification

Hyperkalemia, defined as serum potassium above 5.0 mEq/L, is classified by severity: mild (5.0-5.9 mEq/L), moderate (6.0-6.4 mEq/L), and severe (6.5 mEq/L or higher). This potentially life-threatening electrolyte abnormality requires prompt recognition and treatment.

Before treating hyperkalemia, pseudohyperkalemia must be excluded. This laboratory artifact results from potassium release from cells during or after blood collection. Hemolysis from traumatic phlebotomy releases potassium from red cells. Thrombocytosis and leukocytosis cause potassium release during clot formation in the collection tube; a plasma (anticoagulated) sample will show lower values. Prolonged tourniquet application with fist clenching releases potassium from ischemic muscle. Pseudohyperkalemia should be suspected when hyperkalemia appears unexpectedly in a stable patient without risk factors.

True hyperkalemia results from three mechanisms. Transcellular shift releases intracellular potassium without changing total body content. Mineral acidosis causes hydrogen-potassium exchange. Insulin deficiency reduces sodium-potassium ATPase activity. Beta-blockers impair adrenergic potassium uptake. Cell lysis from rhabdomyolysis, tumor lysis syndrome, or hemolysis releases massive intracellular potassium. Succinylcholine-induced depolarization releases potassium from muscle cells, particularly dangerous in patients with burns, denervation, or prolonged immobility where potassium release is exaggerated. Hyperkalemic periodic paralysis involves mutations causing episodic shifts.

Decreased renal excretion is the most common mechanism in clinical practice. Reduced GFR from acute or chronic kidney disease impairs the filtered load and reduces delivery to secretory sites. Hypoaldosteronism, whether from adrenal insufficiency, hyporeninemic hypoaldosteronism (common in diabetic nephropathy), or medications (ACE inhibitors, ARBs, direct renin inhibitors), reduces potassium secretion. Potassium-sparing diuretics directly block secretion through ENaC (amiloride, triamterene) or the mineralocorticoid receptor (spironolactone, eplerenone). NSAIDs reduce prostaglandin-mediated renin release and directly affect potassium secretion. Trimethoprim blocks ENaC. Reduced tubular flow from severe volume depletion impairs potassium washout.

Increased intake rarely causes hyperkalemia if renal function is normal, as the kidney can excrete hundreds of milliequivalents daily. However, in patients with impaired excretion, excessive intake from supplements, salt substitutes, or blood transfusions (stored blood releases potassium) can precipitate dangerous hyperkalemia.

<image>Panel A: Decision box to first rule out pseudohyperkalemia listing causes (hemolysis, thrombocytosis, leukocytosis, prolonged tourniquet, fist clenching) with note to repeat sample if suspected. Panel B: Transcellular shift showing cell with K+ exiting, listing acidosis (mineral), insulin deficiency, beta-blockers, cell lysis, succinylcholine, hyperkalemic periodic paralysis. Panel C: Decreased excretion (most common) showing kidney with impaired output: reduced GFR, hypoaldosteronism, drugs (ACEi, ARBs, K+-sparing diuretics, NSAIDs, trimethoprim), reduced tubular flow. Panel D: Increased intake showing oral/IV sources noting rarely sole cause if kidneys normal: supplements, salt substitutes, blood transfusion.</image>

Hyperkalemia: ECG Changes and Treatment

Hyperkalemia produces characteristic ECG changes that progress with worsening severity, though the correlation between potassium level and ECG findings is imperfect. Some patients show severe changes at modest potassium elevations, while others tolerate higher levels with minimal ECG abnormality. Therefore, treatment decisions must consider both the laboratory value and the ECG.

The earliest ECG manifestation is peaked T waves, described as tall, narrow, and symmetric, typically appearing at potassium levels of 5.5 to 6.5 mEq/L. As potassium rises further (6.5-7.5 mEq/L), conduction slows, producing prolongation of the PR interval and widening of the QRS complex. At levels of 7.5 to 8.0 mEq/L, P waves may disappear as the atria become inexcitable. Further increases cause the QRS to merge with the T wave, producing the characteristic sine wave pattern that presages ventricular fibrillation or asystole.

Treatment follows a logical sequence: stabilize the membrane, shift potassium into cells, and remove potassium from the body.

Calcium gluconate (or calcium chloride if central access is available) stabilizes the cardiac membrane within minutes by raising the threshold potential, reducing the risk of arrhythmia without altering potassium levels. The effect is temporary (30-60 minutes), buying time for other interventions. This is the first intervention in any patient with ECG changes.

Shifting potassium into cells provides more sustained temporary benefit. Regular insulin (10 units intravenously) with glucose (25-50 grams of dextrose to prevent hypoglycemia) shifts potassium within 10 to 20 minutes, lowering levels for 4 to 6 hours. Beta-2 agonists (high-dose nebulized albuterol) provide additional shift. Sodium bicarbonate has minimal effect in patients without acidosis but helps if acidemia is present.

Removing potassium from the body provides definitive treatment. Loop diuretics increase renal excretion if the patient has reasonable kidney function and is not severely volume-depleted. Potassium binders remove potassium through the gastrointestinal tract: sodium polystyrene sulfonate (Kayexalate) works slowly and has safety concerns including bowel necrosis; newer agents patiromer and sodium zirconium cyclosilicate are better tolerated but take hours to act. Hemodialysis rapidly and definitively removes potassium and is indicated for severe hyperkalemia, renal failure, or refractory cases.

<image>Panel A: ECG strip showing progression with K+ levels: peaked T waves (5.5-6.5), prolonged PR/widened QRS (6.5-7.5), loss of P waves (7.5-8.0), sine wave pattern (>8.0). Panel B: Step 1 STABILIZE showing calcium gluconate 10 mL of 10% IV, onset 1-3 min, duration 30-60 min, protects heart but does not lower K+. Panel C: Step 2 SHIFT showing insulin 10U plus glucose 25-50g onset 10-20 min, albuterol nebulized onset 15-30 min, NaHCO3 if acidotic; Step 3 REMOVE showing furosemide, K+ binders, dialysis for severe/refractory. Panel D: Monitoring box showing continuous ECG, repeat K+ every 1-2 hours, glucose monitoring after insulin.</image>

Special Populations and Drug Effects

Certain patient populations require special consideration for potassium management because of altered physiology or medication effects.

Patients with chronic kidney disease adapt to reduced excretory capacity through increased colonic potassium secretion and enhanced collecting duct secretion per remaining nephron. This adaptation allows tolerance of higher potassium levels than would be expected for the degree of GFR reduction. However, these patients are vulnerable to acute changes: sudden increases in intake, addition of drugs that impair secretion, or acute illnesses can precipitate dangerous hyperkalemia. Management involves dietary potassium restriction and judicious use of potassium-lowering medications.

Diabetic patients face complex potassium dynamics. Type 4 renal tubular acidosis (hyporeninemic hypoaldosteronism) is common in diabetic nephropathy, producing chronic tendency to hyperkalemia. Diabetic ketoacidosis presents a particular challenge: despite total body potassium depletion from osmotic diuresis, the serum potassium may be normal or elevated at presentation due to insulin deficiency and acidosis. Treatment with insulin causes rapid potassium shift into cells, potentially precipitating severe hypokalemia. Potassium should be added to fluids once levels fall below 5.2 mEq/L, and replacement should begin early.

Heart failure patients often take multiple medications with opposing effects on potassium. ACE inhibitors, ARBs, and mineralocorticoid receptor antagonists (spironolactone, eplerenone) all promote hyperkalemia and provide proven mortality benefit, but their combination increases risk substantially. Loop diuretics cause hypokalemia. Achieving the right balance requires careful monitoring.

Numerous medications affect potassium levels. Drugs raising potassium include ACE inhibitors, ARBs, potassium-sparing diuretics, NSAIDs (through reduced renin and direct tubular effects), trimethoprim (blocks ENaC), heparin (reduces aldosterone synthesis), and calcineurin inhibitors. Drugs lowering potassium include loop and thiazide diuretics, insulin, beta-agonists, amphotericin B, and certain chemotherapy agents.

<image>Panel A: CKD patient showing adapted kidney with increased colonic K+ secretion, tolerance of higher K+ but vulnerability to acute changes, dietary restriction and binder strategies. Panel B: Diabetic patient showing DKA scenario with total body K+ depletion but normal/high serum K+, treatment causing rapid drop with early replacement emphasis; type 4 RTA as chronic hyperkalemia risk. Panel C: Heart failure patient showing medication balance scale with ACEi/ARBs/MRAs raising K+ versus loop diuretics lowering K+ with monitoring emphasis. Panel D: Table of medications grouped by whether they raise or lower potassium with mechanisms briefly noted.</image>

Diagnostic Approach

The diagnostic workup for potassium disorders aims to identify the underlying cause and guide treatment.

For hypokalemia, the first step after confirming the value is measuring urine potassium excretion. If urine potassium is low (less than 20 mEq per day or less than 15 mEq/L on a spot sample), the kidney is appropriately conserving potassium and the cause is extrarenal: gastrointestinal losses (diarrhea, fistula) or transcellular shift. If urine potassium is high (greater than 20 mEq per day), the kidney is inappropriately wasting potassium. Further evaluation of renal wasting considers blood pressure (elevated suggests hyperaldosteronism), acid-base status (metabolic alkalosis suggests vomiting, diuretics, or hyperaldosteronism; metabolic acidosis suggests RTA), and magnesium level (hypomagnesemia causes refractory hypokalemia).

For hyperkalemia, the first step is ruling out pseudohyperkalemia by repeating the sample if the finding is unexpected. Next, assess renal function; reduced GFR suggests impaired excretion as the mechanism. Review the medication list for drugs that impair secretion. Check for sources of cellular potassium release (acidosis, cell lysis, recent succinylcholine). If GFR is normal and medications are not causative, consider hypoaldosteronism and check renin and aldosterone levels.

The transtubular potassium gradient (TTKG), calculated as (UK × POsm) / (PK × UOsm), was previously used to assess collecting duct potassium secretion. A TTKG above 4 in hypokalemia suggests inappropriate renal wasting; a TTKG below 5 in hyperkalemia suggests impaired secretion. However, this test has fallen out of favor due to methodological limitations, and direct urine potassium measurement with clinical context is usually sufficient.

<image>Panel A: Hypokalemia workup starting with confirmed low K+, measuring urine K+ and branching to less than 20 mEq/day (extrarenal: GI losses, shift) or greater than 20 mEq/day (renal losses). Panel B: Renal loss workup checking BP for hyperaldosteronism, acid-base for RTA, Mg2+ for hypomagnesemia. Panel C: Hyperkalemia workup starting with elevated K+, decision point for unexpected leading to repeat sample, then checking GFR, reviewing medications, assessing for cell lysis/acidosis, considering hypoaldosteronism. Panel D: Urine K+ interpretation table with values and meaning; note that TTKG is less commonly used now.</image>

Summary

• Potassium is 98% intracellular; the steep gradient determines resting membrane potential and excitability
• Internal balance: insulin and beta-2 agonists shift potassium into cells; acidosis, insulin deficiency, and cell lysis shift it out
• External balance: the kidney adjusts excretion; the collecting duct principal cell is the regulatory site
• Potassium secretion is increased by aldosterone, high tubular flow, high sodium delivery, and alkalosis
• Hypokalemia causes include GI losses, diuretics, and hyperaldosteronism; ECG shows U waves and flattened T waves
• Hypomagnesemia must be corrected for potassium repletion to succeed
• Hyperkalemia causes include decreased excretion (most common), transcellular shift, and increased intake; ECG shows peaked T waves progressing to sine waves
• Treatment of hyperkalemia: calcium to stabilize, insulin and albuterol to shift, diuretics, binders, or dialysis to remove
• CKD patients adapt to higher potassium but are vulnerable to acute changes; diabetic patients in DKA need careful potassium monitoring

Key Terms

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