Hyperkalemia pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Jogeet Singh Sekhon

Overview

Potassium is the most abundant intracellular cation and is critically important for many physiologic processes. The normal range of potassium in blood is 3.5-5.1mEq/L. Hyperkalemia develops when the level of potassium exceeds 5.5 mEq/L in blood which can be due to an increase in intake of potassium, excessive production as seen in tissue breakdown, ineffective elimination of potassium or some drugs. The potassium levels in the body are highly regulated mainly by renal excretion. The gut excretes a minimal amount of dietary potassium (approximately 10%). Hyperkalemia is very common in patients with chronic kidney disease as potassium is not effectively excreted from the body. Potassium is involved in maintaining transmembrane potential of the cells, so imbalance in potassium levels can lead to disruption of cell membrane potentials and can cause hyperexcitablity leading to fatal cardiac arrhythmias and may affect the nervous system.

Pathophysiology

Physiological role of potassium

Potassium is the major intracellular cation and sodium is the major extracellular cation. Almost all cells possess an Na⁺-K⁺-ATPase, which pumps Na⁺ out of the cell and K⁺ into the cell and leads to a K⁺ gradient across the cell membrane (K⁺in>K⁺out) that is partially responsible for maintaining the potential difference across the membrane. This potential difference called the transmembrane potential is responsible for the excitability of the cells.

Sodium-Potassium-ATPase Pump Source: Courtesy of Mariana Ruiz Villarreal, via Wikimedia commons

Factors affecting transcellular shift of potassium

The distribution of potassium inside and outside the cells is maintained by various pumps, osmolarity, pH and the hormones including insulin, aldosterone, catecholamines and prostaglandins.

• Insulin regulates potassium uptake into the cells through GLUT receptors on the cell membranes by increasing the activity of Na⁺-K⁺-ATPase pump.

• Catecholamines regulate potassium uptake into the cells through β2-Receptor–induced stimulation of Na⁺K⁺ATPase pump.
• Increased osmolarity as in hyperglycemia causes water efflux from the cells that drags potassium along.
• In acidosis, the decreased extracellular pH decreases the rate of Na+-H⁺ exchange (NHE1) and inhibit the inward rate of sodium bicarbonate(NaHCO3) cotransport,thus decreasing intracellular Na⁺ levels which in turn decreases the activity of Na^+-K⁺-ATPase pump and decreasing intracellular K⁺ levels.
• In alkalosis, the increased extracellular pH increases the rate of NHE1 and increases the inward rate of NaHCO3 cotransport,thus increasing intracellular Na⁺ levels which in turn increases the activity of Na^+-K^+-ATPase pump and increasing intracellular K⁺ levels.

Role of kidneys

• The potassium levels in the body are dependent on dietary intake, tissue breakdown, gastrointestinal absorption and losses and most important is renal regulation via absorption and secretion. Kidneys play an important role in keeping the balance of potassium.

• At the glomerulus, potassium is freely filtered and then largely reabsorbed in the proximal tubule and thick ascending loop of Henle (>60 % of filtered potassium).
• The cortical collecting duct receives 10–15% of filtered potassium and constitutes the kidney’s major site of potassium excretion.
• Potassium excretion at the cortical collecting duct depends on the amount of sodium delivered there and the activity of aldosterone. It does so by the following ways.
  • Increases intracellular K⁺ concentration by stimulating the activity of the Na^+-K^+-ATPase at the basolateral membrane.
  • Stimulates Na⁺ reabsorption across the luminal membrane, which increases the electronegativity of the lumen, thereby increasing the electrical gradient favoring K⁺ secretion. If the rate of delivery of sodium and water is very high in the distal tubules then it will cause more Na⁺ reabsorption and more K⁺ secretion.
• Has a direct effect on the luminal membrane to increase K⁺ permeability.

• Alteration in the levels of potassium occur due to disruption in the above mentioned mechanisms that regulate potassium homeostasis.

Pathogenesis

• Hyperkalemia means excessive potassium in the blood(>5.1 meq/L).
• It can result from excessive potassium intake, increased tissue breakdown, increased transcellular shift or impaired excretion from the body .

Increased uptake

• The only source of potassium to our body is by diet. If potassium rich diet is consumed or given parenterally, it can lead to hyperkalemia. However, in individuals with normal renal function, potassium levels are regulated and excess potassium is excreted.

Transcellular shift

• Change in extracellular pH-decrease in pH as in mineral acidosis leads to increased shift of potassium from intracellular to extracellular space.
• Decrease in insulin as in diabetes mellitus, can lead to increased extracellular accumulation of potassium.
• Increase in osmolarity as in hyperglycemia, will cause extracellular shift of potassium.
• Decreased catecholamines or reduced function as with beta blockers use will lead to decreased uptake by cells resulting in extracellular accumulation of potassium.

Tissue breakdown

• Increased tissue breakdown can occur as in rhabdomylosis, burns, haemolytic conditions or chemotherapy induced tissue breakdown.

• Pseudohyperkalemia referred to as increased serum potassium levels but plasma potassium levels are within range.This usually occurs invitro while collecting a blood sample, thrombocytosis or in myeloproliferative diseases.

Impaired excretion

• Potassium levels in body are regulated by the kidneys. Any impairment in the excretion mechanisms can result in hyperkalemia.
• Reduced GFR(<15ml/min) results in decreased urine flow and hence decreased sodium and water delivery to the distal tubules resulting in decreased secretion of potassium.
• Decrease in the levels of aldosterone as in primary hypoaldosteronism and secondary hypoaldosteronism results in impaired excretion of potassium.
• Pseudohypoaldostrenism- the levels of aldosterone are within normal limits but there is resistance to aldosterone in the kidneys and is not able to exert its function.
• Chronic kidney disease- the overall renal function is impaired resulting in decreased secretion of potassium as in various nephropathies.
• Renal parenchymal damage- this can occur in obstructive uropathy or AKI in which the renal parenchyma would not be able to effectively excrete potassium.
• Constipation-minor amount of potassium is also excreted by stools,so chronic constipation can lead to hyperkalemia however it is very rare.

Trans-cellular shifts	Renal secretion impairment		GI cause	Increased tissue breakdown	Increased intake of potassium
Metabolic acidosis (K+/H+ exchanger) Diabetic ketoacidosis (Insulin activates Na+/K+ ATPase) Beta blockers (catecholamines activate Na+/K+ ATPase) Hyperkalemic thyrotoxic periodic paralysis Hyperosmolarity Hypothermia	Renal parenchymal damage Nephropathies Acute kidney injury Obstructive uropathy Amyloidosis Glomerulonephritis Polycystic kidney disease Tubulointerstitial disease	Defect in Potassium secretion Primary hypoaldosteronism Addison's disease Autoimmune adrenalitis Congenital adrenal hyperplasia ACTH deficiency Secondary hypoaldosteronism Renal tubular acidosis Hyporenimin hypoaldosteronism ACE inhibitors Pseudohypoaldosteronism Dehydration, Heart failure	Constipation	Rhabdomyolysis Tumor lysis syndrome Snake bite	Potasium rich diet-Spinach,green leafy vegetables,lettuce Potassium supplements Parenteral potassium citrate or potassium chloride

Drugs causing hyperkalemia

A lot of drugs are responsible for causing hyperkalemia. They do so by multiple mechanisms which are listed below:

Drug	Mechanism causing hyperkalemia
Amiloride	Blocking sodium channels of luminal membrane of principal cells
Spironolactone	Mineralocorticoid receptor antagonist (competing with aldosterone)
Beta Blockers	Decrease in cellular potassium uptake
Calcium channel blockers	Inhibition of adrenal aldosterone biosynthesis
Succinylcholine	Leakage of potassium out of cells through depolarization of cell membranes
Mannitol	*Potassium shifts out of cells due to the body’s attempt to maintain isotonicity while undergoing a hypertonic infusion
Heparin	Inhibition of adrenal aldosterone biosynthesis
Digoxin	Inhibition of Na+/K+-ATPase
ACE inhibitors	Reduction in adrenal aldosterone biosynthesis through interrupting renin-aldosterone axis and reduction in effective GFR
Angiotensin receptor-II antagonists	Reduction in adrenal aldosterone biosynthesis through interrupting renin-aldosterone axis and reduction in effective GFR
NSAIDs	Reduction in adrenal aldosterone biosynthesis through interrupting renin-aldosterone axis and reduction in effective GFR
Cyclosporine,tacrolimus	Inhibition of adrenal aldosterone biosynthesis
Trimethoprine	Blocking of sodium channels in the luminal membrane of principal cells

Effects of hyperkalemia

• Potassium is vital for maintaining the membrane potential difference of cells. Increase in blood potassium levels lead to disruption in transmemebrane potential difference.

• Hyperkalemia will depolarize the cells, thus the cells will remain excited initially.
• However, persistent depolarization will deactivate the sodium channels and sodium would not move inside the cells.
• Inability of sodium to move inside the cells will cause them to become refractory to the stimulation.
• The cells would not respond to the electric signal and will remain in a depolarized state.

Effect on heart:

• Hyperkalemia can cause fatal cardiac arrhythmias in the form of ventricular fibrillation or even cardiac arrest.
• It effects the cardiac muscle by:
  • Prolongation of membrane depolarization
  • Slower myocardial conduction
  • Shortening of the repolarization time
• This will result in peaked T waves, loss of P wave, PR interval prolongation, sine wave pattern and widening of QRS complex.

• Nervous system and muscle are effected in the same manner resulting in muscle weakness and fatigue.

Genetics

Genetic conditions associated with hyperkalemia include:

• Hyperkalemic periodic paralysis
  • Hyperkalemic PP is an autosomal dominant condition with complete penetrance. The cause of hyperkalemic PP is a change in a gene that regulates the production of a protein (SCN4A) in the sodium channel of skeletal muscle. The gene is located in chromosome 17q23, and is known as SCN4A.
  • There is a defect in the sodium channels and sodium continues to leak out resulting in paralysis of the muscle.
  • During the episode of muscle paralysis,potassium leaks out into the bloodstream causing hyperkalemia.

• Congenital adrenal hyperplasia
  • Congenital adrenal hyperplasia consists of several disorders resulting from defective enzymes and proteins involved in steroid and cortisol synthesis pathways. Defects in steroid biosynthesis are caused by several genetic mutations and may lead to delayed puberty, precocious puberty or ambiguous genitalia in specific disorders.
  • In 21 hydroxylase deficiency there is decreased production of aldosterone and hence hyperkalemia occurs.
  • In 3 beta hydroxysteroid dehydrogenase deficiency decreased production of aldosterone causes hyperkalemia.

Gross pathology

• There is as such no gross changes in pathology in hyperkalemia. It usually depends on the underlying condition causing hyperkalemia.

Microscopic pathology

• There is as such no microscopic changes in pathology in hyperkalemia. It usually depends on the underlying condition causing hyperkalemia.