1. Epidemiology and Clinical Significance

Potassium disorders are common in critically ill and chronic disease populations and demonstrate a U-shaped mortality curve. Monitoring and early intervention are essential to prevent arrhythmias and organ dysfunction.

1.1 Prevalence in Key Populations

• Hypokalemia (<3.5 mEq/L): Affects approximately 1.9% of the general population, but prevalence rises to 7–10% in ICU patients, often due to diuretics and acid–base shifts.
• Hyperkalemia (>5.0 mEq/L): Found in about 3.3% of the general population. The rate increases significantly to 18% in patients with CKD stages 3–5 and around 10% in heart failure patients on RAAS inhibitors.
• COVID-19: In ICU cohorts, hypokalemia was observed in about 24% and hyperkalemia in 4% of admissions, both correlating with worse outcomes.

1.2 U-Shaped Relationship Between Serum K⁺ and Mortality

Both low and high potassium levels are associated with increased mortality, forming a U-shaped risk curve. The optimal range is generally considered 4.0–5.0 mEq/L for most patients, though heart failure patients may tolerate levels up to 5.2 mEq/L. Deviations from this range, both hypokalemia (<3.5 mEq/L) and hyperkalemia (>5.0 mEq/L), confer a 15–20% relative increase in mortality for each 1 mEq/L change. This risk is particularly pronounced in patients with CKD, highlighting their narrow therapeutic window.

2. Physiology and Pathophysiology of Potassium Homeostasis

The total body potassium content is approximately 50 mEq/kg, with 98% located intracellularly. The kidneys are responsible for fine-tuning excretion, while hormones and acid–base status govern the rapid transcellular shifts between intracellular and extracellular compartments.

2.1 Intracellular vs. Extracellular Distribution

The body maintains a steep concentration gradient, with intracellular potassium at ~140 mEq/L and extracellular potassium at only ~4 mEq/L. This gradient, crucial for neuromuscular function, is actively maintained by the Na⁺/K⁺-ATPase pump, which is stimulated by insulin and β₂-agonists.

2.2 Renal Handling: Filtration, Reabsorption, and Secretion

• Proximal Tubule: About 65% of filtered potassium is reabsorbed passively along with water (solvent drag).
• Thick Ascending Limb of Henle: Another 25% is reabsorbed via the Na⁺-K⁺-2Cl⁻ cotransporter (NKCC2). Loop diuretics block this transporter, leading to increased potassium excretion (kaliuresis).
• Distal Nephron (DCT/CCD): This is the primary site of regulated potassium secretion. Principal cells secrete potassium into the tubular lumen through ROMK and Maxi-K channels. This process is driven by the electronegative lumen potential created by sodium reabsorption via the ENaC channel.

The ‘Potassium Switch’ Mechanism

The aldosterone paradox describes how the distal nephron responds differently to volume depletion versus hyperkalemia. In volume depletion, aldosterone primarily enhances sodium retention with minimal potassium loss. In isolated hyperkalemia, it preferentially stimulates potassium secretion without causing fluid overload.

2.3 Endocrine Regulation

• Aldosterone: The primary hormonal regulator of potassium excretion, it upregulates both ENaC and ROMK channels in the principal cells of the distal nephron.
• Insulin & β₂-Agonists: These hormones promote rapid shifting of potassium into cells by stimulating the Na⁺/K⁺-ATPase pump.

2.4 Acid–Base Influences

Systemic pH significantly influences extracellular potassium concentration. In metabolic acidosis, excess H⁺ ions enter cells in exchange for K⁺, causing hyperkalemia. Each 0.1 unit drop in pH can raise serum potassium by approximately 0.6 mEq/L. Metabolic alkalosis has the opposite effect, driving potassium into cells and causing hypokalemia.

3. Impact of Pre-Existing Chronic Diseases

Chronic conditions like CKD, heart failure, and diabetes fundamentally alter potassium handling and hormonal responsiveness, creating a high-risk environment for dyskalemia.

3.1 Chronic Kidney Disease (CKD)

As GFR falls below 20 mL/min/1.73 m², the reduced nephron mass becomes inadequate for sufficient potassium excretion. Chronic mild hyperkalemia (5.0–5.5 mEq/L) is common and often managed with dietary restrictions and potassium binders.

3.2 Heart Failure

Patients with heart failure face a dual risk. The underlying disease upregulates the RAAS, predisposing to hyperkalemia, a risk compounded by the use of RAAS inhibitors. Simultaneously, treatment with loop and thiazide diuretics causes significant potassium loss, leading to wide and dangerous swings in serum levels.

3.3 Diabetes Mellitus

• Type 1 Diabetes: Absolute insulin deficiency impairs cellular potassium uptake, increasing the risk of hyperkalemia, especially with glucose fluctuations.
• Type 2 Diabetes: Insulin resistance and associated autonomic neuropathy blunt the β₂-agonist-mediated cellular uptake of potassium, also predisposing to hyperkalemia.

4. Social Determinants of Health as Risk Modifiers

Patient outcomes are not solely determined by physiology. Access to care, health literacy, and cultural factors significantly shape adherence to potassium-modifying therapies and dietary recommendations.

4.1 Medication Access & Affordability

Newer, safer potassium binders like patiromer and sodium zirconium cyclosilicate are often cost-prohibitive for many patients. This can lead to reliance on older agents like sodium polystyrene sulfonate (SPS), which carries a significant risk of gastrointestinal toxicity, including colonic necrosis.

4.2 Health Literacy & Dietary Compliance

Misunderstanding of dietary sources can lead to dangerous potassium levels. Patients may not recognize hidden sources of potassium, such as salt substitutes (which often contain potassium chloride), processed foods, and certain herbal products, leading to unrecognized hyperkalemia.

4.3 Socioeconomic & Cultural Factors

Living in “food deserts” with limited access to fresh produce can increase the risk of hypokalemia. Conversely, cultural diets rich in fruits and vegetables, while generally healthy, may predispose patients with advanced CKD to severe hyperkalemia.

5. Clinical Presentation

Symptoms of potassium disorders range from asymptomatic lab findings to severe neuromuscular weakness and life-threatening cardiac arrhythmias. While the ECG is a helpful tool, it lacks sensitivity, especially in chronic conditions.

5.1 Neuromuscular Manifestations

• Hypokalemia: Can cause muscle cramps, weakness, and in severe cases (<2.5 mEq/L), paralytic ileus and rhabdomyolysis.
• Hyperkalemia: Often presents with paresthesias and can progress to ascending paralysis that mimics Guillain-Barré syndrome.

5.2 Cardiac Manifestations & ECG Patterns

The ECG provides critical clues to the severity of dyskalemia. However, changes do not always correlate with the serum level.

• Hypokalemia: Characterized by flattened T waves, prominent U waves, and ST-segment depression.
• Hyperkalemia: Progresses through a classic sequence: peaked T waves → PR interval prolongation → widened QRS complex → sine wave pattern → asystole.

5.3 Subclinical and Incidental Detection

Most cases of dyskalemia are identified through routine laboratory testing rather than clinical symptoms. The advent of point-of-care testing and telemetry-linked biochemistry monitoring is enabling earlier detection and intervention in high-risk settings.