Disorders of Potassium Balance

Pooja Koolwal

Andreas Herrlich

General Principles

Total body potassium (K⁺) is about 50 mEq/kg, 98% of which is intracellular. Intracellular [K⁺] are about 140 mEq/L, approximately 35 times the normal extracellular (or plasma) value of about 4 mEq/L.
Normal daily K⁺ intake can vary widely and requires tight regulation of plasma concentration. Changes in plasma [K⁺] may occur due to K⁺ shifting into or out of cells, independent of body K⁺ stores, see Table 4-1.
K⁺ elimination primarily occurs through the kidneys, though some stool elimination occurs (about 10 mEq/day) as well. Minimal K⁺ is lost through sweat.

Renal potassium regulation:

Potassium is freely filtered at the glomerulus and 67% is reabsorbed at the proximal convoluted tubule, while 20% is reabsorbed in the thick ascending loop of Henle. Tight regulation occurs in the distal tubule and collecting duct.
Aldosterone plays a central role in [K⁺] regulation by stimulating its excretion in the cortical collecting duct of the nephron.

Hyperkalemia also directly stimulates renal K⁺ secretion, which is dependent on adequate tubular flow in the distal nephron.

TABLE 4-1 FACTORS AFFECTING TRANSCELLULAR K⁺ SHIFT

Physiologic

Pathologic

Na⁺/K⁺ ATPase

Maintains high intracellular K⁺ gradient

Catecholamines

α-adrenergic—impairs K⁺ entry into cells
β₂-adrenergic—promotes K⁺ entry into cells

Insulin

Promotes K⁺ entry into cells
Insulin deficiency impairs K⁺ entry into cells

Exercise

Causes K⁺ release from cells for local vasodilation and increased blood flow

Extracellular pH

Acidosis—pH decreases and H⁺ will move into cells in exchange for K⁺ shifting out of cells
Alkalosis—pH increases and H⁺ will move out of cells in exchange for K⁺ shifting into cells

Hyperosmolarity

Increased intracellular [K⁺] drives K⁺ out of cells down chemical gradient

Cell turnover

Increase cell breakdown—K⁺ released from cells
Increased cell production—K⁺ is rapidly taken up by cells

Decreased effective circulating volume (ECV) will increase aldosterone production and increase potassium secretion in exchange for sodium retention. But decreased ECV also decreases distal flow rate, which leads to reduced K⁺ excretion. This
generally allows plasma [K⁺] to remain at stable concentrations within certain limitations (please see Fig. 4-1). However, when potassium secretion is impaired by, for example, an angiotensin receptor blocker (ARB) or angiotensin-converting enzyme (ACE) inhibitor, or if dehydration is severe because the patient is taking a diuretic, these limitations can become relevant and plasma [K⁺] can rise above normal levels.

FIGURE 4-1. Extracellular volume effect on potassium concentration.

Hypokalemia

General Principles

Definition

Hypokalemia is defined as [K⁺] <3.5 mEq/L.

Pathophysiology

Hypokalemia may result from decreased intake, intracellular shift, or increased renal or gastrointestinal (GI) losses.

Decreased intake: In the setting of decreased intake, the normally functioning kidney can decrease K⁺ excretion to <25 mEq/day. Moderate dietary K⁺ restriction alone does not cause hypokalemia.
Intracellular shift: Please refer back to Table 4-1.
- Alkalosis—promotes K⁺ shift into cells and H⁺ movement out of cells.
- Stimulation of the Na⁺/K⁺-ATPase pump—activity can be increased by catecholamines, particularly β₂-adrenergic stimulation and insulin. It can also mediate hypokalemia often seen with refeeding syndrome.
- Treatment of anemia or neutropenia—increased hematopoiesis after vitamin B₁₂/folic acid for megaloblastic anemia or granulocyte-macrophage colony-stimulating factor (GM-CSF) for neutropenia can cause increased K⁺ uptake.
- Hypokalemic periodic paralysis—results from rapid K⁺ shifting into skeletal muscle cells (often after exercise, large carbohydrate meal, or insulin dose). It results from a defect in dihydropyridine-sensitive calcium channels of skeletal muscles, which can either be inherited in an autosomal dominant pattern or acquired, as in thyrotoxicosis.
- Hypothermia. Hypothermia is believed to cause an influx of potassium into the intracellular space. Of note, in severe hypothermia, hyperkalemia can be seen due to tissue ischemia and is highly correlated to terminal hypothermia.
Increased GI losses (normal fecal K⁺ losses are around 10 mEq/day):
- With normal dietary K⁺ intake, if fecal losses exceed ∼55 mEq/day, the kidney’s ability to conserve K⁺ can be exceeded and K⁺ depletion will occur.
- Large volume stool output of any cause may thus cause hypokalemia.
- Gastric secretions contain very little K⁺. In the case of significant vomiting or large-volume nasogastric suction, hypokalemia is NOT due to K⁺ loss in the gastric fluid.
  Proton loss and volume contraction cause metabolic alkalosis. Although some intracellular shift of K⁺ from alkalemia occurs, the key factor in the development of hypokalemia in these cases is bicarbonaturia and hypovolemia-induced aldosterone release, which enhances K⁺ excretion in the distal nephron.
Increased renal losses:
- Diuretics: Loop and thiazide diuretics increase distal nephron sodium delivery and water excretion. The ensuing hypovolemia induces aldosterone secretion. Both of these effects lead to hypokalemia. Bartter and Gitelman syndromes are loss-of-function mutations in furosemide- and thiazide-sensitive channels, respectively.
- Syndromes of mineralocorticoid excess:
  - Primary hyperaldosteronism (Conn syndrome) due to adrenal adenoma or hyperplasia
  - Secondary hyperaldosteronism due to renal artery stenosis, fibromuscular dysplasia, renin-secreting tumor (rare)
  - Apparent mineralocorticoid excess
    - 11β-Hydroxylase deficiency—cortisol is a potent mineralocorticoid, but is inactivated in the kidney by 11β-hydroxysteroid dehydrogenase. Licorice (found in chewing gum and tobacco) can inactivate this enzyme, thereby increasing cortisol activity.
    - Cushing syndrome—hypokalemia results from the excess production of steroids that are normally metabolized by 11β-hydroxysteroid dehydrogenase enzyme.
  - Liddle syndrome, a gain-of-function mutation of distal epithelial Na⁺ channels (ENaC), increases sodium reabsorption in the collecting duct and enhances the excretion of potassium
  - Glucocorticoid remediable hyperaldosteronism is the result of a mutation that causes aldosterone production to be stimulated by ACTH. This results in increased aldosterone production, remediable by suppressing ACTH synthesis using glucocorticoids
- Increased distal nephron flow: This can result from saline diuresis, diuretics, salt-wasting nephropathy, and glucosuria (diabetes mellitus or Fanconi syndrome).
- Nonreabsorbable anion: The presence of a nonreabsorbable anion in the distal nephron creates negative charge in the lumen, promoting K⁺ secretion. This phenomenon can be seen with bicarbonaturia (metabolic alkalosis) and urinary hippurate (from glue sniffing).
- Tubular toxins: Amphotericin, gentamicin, hypercalcemia, and cisplatin all cause tubular damage, impairing K⁺ reabsorption.
- Hypomagnesemia: Hypomagnesemia can cause urinary K⁺ wasting and refractory hypokalemia. Adequate renal potassium retention cannot take place before a magnesium deficit is corrected. Hypomagnesemia is often seen with alcoholism, diuretics, diarrhea, malnutrition, aminoglycosides, and cisplatin use.

Diagnosis

Clinical Presentation

Mild hypokalemia (3.0 to 3.5 mEq/L) is generally asymptomatic, although it does pose an increased risk of arrhythmias and increased mortality in patients who also have cardiovascular disease or who are on digitalis.
Weakness and muscle pain or cramps, usually occur initially involving the lower extremities and can develop as the [K⁺] drops below 3 mEq/L.
Decrease in K⁺ to below 2.5 mEq/L can lead to paralysis, including respiratory muscle paralysis. Some patients can present with an ileus due to effects of hypokalemia on smooth muscle. Rhabdomyolysis can occur with severe hypokalemia. However,
rhabdomyolysis in itself elevates plasma [K⁺] and prevents further decrements, possibly masking the underlying etiology. Checking serum creatine phosphokinase (CPK) levels may aid in the diagnosis of suspected hypokalemia-induced rhabdomyolysis.
Hypokalemia can impair renal water reabsorption and cause nephrogenic diabetes insipidus.
Prolonged hypokalemia can cause irreversible interstitial nephritis, renal cysts, hypertension, and glucose intolerance.

Physical Examination

Physical examination findings should focus on signs of volume depletion (volume contraction may lead to metabolic alkalosis and hypokalemia) or hypertension (suggesting mineralocorticoid excess).

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