To understand the pathogenesis or the manner in which hyperkalemia develops in blood, you need to know how and where potassium is stored in the body. This will help you understand the reasons that cause your potassium levels to rise in the blood.

Potassium enters the body through oral intake or intravenous infusion in the hospital. It is mostly stored in all types of living cells of the body (about 98%) including those of the bones. Blood contains only 2% of the body’s potassium.

Approximately 10% of the daily potassium intake is cleared via the gastrointestinal tract. The rest of the extra potassium is got rid of through the urine.

Broadly, hyperkalemia occurs as a result of 3 reasons:

  1. Excessive potassium intake or infusion of potassium-containing substances
  2. Disturbed cellular uptake of potassium, or
  3. Impaired renal excretion of potassium.

Of these, the major causes of hyperkalemia are increased potassium release (or leakage) from the body cells into the blood and, most commonly, its reduced urinary excretion.

Causes of high potassium (Pathogenesis)

The most common causes of hyperkalemia include:

Impaired kidney function

Kidney dysfunction is the major cause of high potassium levels in the blood. Due to impaired function, the kidneys do not filter the blood efficiently. Instead of the excess potassium being removed from the blood and excreted through urine, it builds up in the blood.

Too much potassium accumulation in the blood can happen when your kidneys are diseased and do not function well. Balancing the levels of potassium in the body is an important function of the kidneys.

The normal functioning kidneys excrete out the extra potassium through the urine and this is what keeps the potassium levels within normal limits in a healthy individual.

When the kidneys are fired as in chronic kidney disease (CKD) or renal failure, the kidney function suffers and they are not able to excrete the extra amount of potassium from the body.

Dietary causes

Some foods are high in potassium content. Eating too much of these foods can increase the potassium in the body, especially in those people who have chronic kidney problems.

With normal kidney function, this rarely happens. However, with impaired kidney function (with GFR<1.6 ml/min), a slight increase in potassium intake can cause severe hyperkalemia.

Common foods that fall in this category include cantaloupe, honeydew melon, orange juice, and bananas.

Drug-induced causes

Many drugs can cause hyperkalemia by a number of mechanisms.

They can interfere with potassium stable levels either by promoting transcellular potassium shift or by impairing renal potassium excretion. They can also increase potassium intake by excessive supply because of their high potassium content.

Oral and parenteral administration of potassium is a very common cause of sudden hyperkalemia in hospitalized patients. Intravenous intake can rapidly increase the potassium level and can cause severe hyperkalemia and death.

35% to 75% of hospitalized patients develop hyperkalemia due to these culprit medications. Kidney disease and elderly patients above 60 years of age were the main predisposing risk factors.

Drugs that can induce hyperkalemia include:

  • Blood pressure medicines called angiotensin-converting enzyme (ACE) inhibitors and angiotensin 2 receptor blockers (ARBs) cause hyperkalemia by a variety of reasons including causing abrupt changes and reduction of both glomerular filtration rate (GFR) and aldosterone secretion. Since aldosterone is responsible for increasing potassium excretion, therapy with ACE inhibitors and ARBs can cause the retention of potassium.
  • Beta-blockers, when used in patients with renal dysfunction or insulin insufficiency can potentially cause hyperkalemia. Hyperkalemia can occur in 1% to 5% of patients on beta blockers.
  • Potassium-sparing diuretics such as spironolactone given for high blood pressure can cause high potassium, especially in those with impaired kidney function.
  • Non-steroidal anti-inflammatory drugs (NSAIDs) promote the development of hyperkalemia by two ways:
    • they lower renal renin secretion, and
    • they decrease angiotensin II-induced aldosterone release. The resulting fall in aldosterone secretion reduces urinary potassium excretion, which will cause the plasma potassium concentration to increase.
  • Tacrolimus (FK506) and cyclosporine (cyclosporin A, CsA) are key immunosuppressive agents given to organ transplant recipients to prevent and treat tissue rejection.
  • Pentamidine is an antimicrobial medication used to treat trypanosomiasis, leishmaniasis, and babesiosis, and to prevent and treat pneumocystis pneumonia in people with AIDS who have poor immune function. Pentamidine exhibits more nephrotoxic properties in AIDS patients and can cause life-threatening hyperkalemia.
  • Heparin is a medication, which is used as an anticoagulant. It is also called a blood thinner medication. It is specifically used to treat and prevent deep vein thrombosis, pulmonary embolism, and arterial thromboembolism. However, heparin-induced hypoaldosteronism leading to hyperkalemia is an uncommon side effect. Patients on prolonged heparin therapy or those unable to adequately increase renin production such as patients with diabetes or kidney dysfunction may exhibit complications of hypoaldosteronism, of which hyperkalemia is a major one.
  • Cotrimoxazole (trimethoprim-sulfamethoxazole) is a combination antibiotic used in the treatment of infections mainly those of the urinary bladder, middle ear, and traveler’s diarrhea. Hyperkalaemia has been shown to occur with the administration of high and standard dosages of trimethoprim. Trimethoprim was found to reduce potassium excretion through the kidneys in a way similar to the potassium-sparing diuretic amiloride. Higher dosages and underlying renal impairment are the main risk factors.
  • Potassium supplements given to unmonitored patients cause hyperkalemia in 15% to 40% of hospitalized patients.


It is a well-known fact that acid-base balance and potassium homeostasis are strongly linked.

Acidosis is a condition in which the pH of the blood falls and there is too much acid in your body. This is not a healthy condition and can cause a lot of problems.

Acidosis, more likely mineral acidosis, causes the shift of the potassium from the inside of the body cells (intracellular) to outside the cells (extracellular) into the plasma causing a rise in the levels of potassium inside the blood.

Potassium shifts outside for the exchange of hydrogen ions, which move into the cells.

There are several reasons such as dehydration, preexisting renal disease, hypercatabolism, diabetes mellitus, hypoaldosteronism, and some treatments that can cause acidosis.

Endocrine causes

Addison’s disease is an usually progressive dysfunctioning of the adrenal cortex. The electrolyte disturbances in this condition are due to diminished secretion of cortisol and aldosterone.

The major function of aldosterone is to increase the urinary secretion of potassium. Therefore, hypoaldosteronism is often associated with hyperkalemia and mild metabolic acidosis.

Diabetes mellitus

Poorly controlled diabetes is often a cause of chronic hyperkalemia. Electrolyte disorders are often seen in diabetes, which is not controlled.

The most important factor responsible for chronic hyperkalemia in diabetic individuals is the syndrome of hyporeninemic hypoaldosteronism (SHH).

SHH is a common illness characterized by hyperkalemic, hyperchloremic (high chloride ions in the blood) metabolic acidosis. It is usually associated with mild or moderately advanced renal insufficiency.

Hypertonicity of muscles and insulin deficiency are other factors responsible for the development of hyperkalemia in diabetics.

Salt substitutes

Salt substitutes and salt alternatives, recommended for patients with high blood pressure and edema, contain a significant amount of potassium. Some such substitutes contain 10 to 13 mEq of potassium per gram. Indiscriminate use can cause your potassium levels to increase.

Burns and severe injuries

Burns and severe injuries cause hyperkalemia because your body responds to these emergencies by releasing extra potassium from the cells into your blood. Destruction of red blood cells in such conditions as burns also releases potassium from the broken-down cells into the bloodstream.

Alcoholism and drug abuse

Alcoholism or heavy drug use causes rhabdomyolysis, which involves the breakdown of muscle fibers. This causes the release of potassium from the muscle cells into the bloodstream.