What causes hyperkalemia and hyponatremia in patients, particularly those with kidney disease or heart failure?

What Causes Hyperkalemia and Hyponatremia

Causes of Hyperkalemia

Hyperkalemia results from three fundamental mechanisms: decreased renal potassium excretion (the dominant cause), transcellular shift of potassium out of cells, or excessive potassium intake—with impaired renal excretion being the most important in clinical practice. 1

Decreased Renal Potassium Excretion

• Chronic kidney disease is the most common cause, with hyperkalemia incidence increasing dramatically as eGFR declines—occurring in up to 73% of patients with advanced CKD. 1 Risk progressively increases when eGFR falls below 60 mL/min per 1.73 m², and is generally elevated once eGFR is less than 15 mL/min per 1.73 m². 1

• Acute kidney injury is often accompanied by acute pancreatitis or hepatic failure, and was present in all cases of hyperkalemia-induced cardiac arrest in one retrospective analysis. 1

• Medications represent the most important iatrogenic cause in everyday clinical practice:

  • RAAS inhibitors (ACE inhibitors, ARBs, mineralocorticoid receptor antagonists) cause hyperkalemia in up to 40% of heart failure patients and 5-10% with combination therapy. 1, 2
  • Potassium-sparing diuretics (spironolactone, triamterene, amiloride) directly impair renal potassium excretion. 1
  • NSAIDs impair renal potassium excretion by reducing prostaglandin synthesis. 1
  • Trimethoprim and pentamidine block epithelial sodium channels in the collecting duct. 1
  • Heparin and derivatives suppress aldosterone synthesis. 1

Transcellular Potassium Shift

• Metabolic acidosis causes potassium to shift out of cells in exchange for hydrogen ions. 1

• Insulin deficiency impairs cellular potassium uptake via Na/K-ATPase. 1

• Massive tissue breakdown releases large amounts of intracellular potassium:

  • Rhabdomyolysis 1
  • Tumor lysis syndrome 1
  • Severe burns 1

• Hemolysis can occur in the body (true hyperkalemia) or in the test tube (pseudohyperkalemia). 1

Excessive Potassium Intake

• Potassium supplements are a direct exogenous source. 1

• Salt substitutes often contain potassium chloride (e.g., DASH diet products). 1

• High-potassium foods include bananas, melons, orange juice, potatoes, and tomatoes. 1

High-Risk Patient Populations

• Advanced CKD, heart failure, diabetes mellitus, and advanced age have dramatically elevated risk of developing hyperkalemia. 1 Men have slightly higher risk than women after RAAS inhibitor initiation. 1

• Multiple mechanisms often coexist, such as CKD + RAAS inhibitor + NSAID, which compounds the risk. 1

Pseudohyperkalemia

• Falsely elevated potassium in the test tube without true elevation in the body can be caused by:

  • Hemolysis during blood draw 1
  • Prolonged tourniquet application 1
  • Fist clenching during phlebotomy 1
  • Thrombocytosis or leukocytosis 1

• If pseudohyperkalemia is suspected, repeat measurement with proper blood sampling technique or obtain an arterial sample for confirmation. 1

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Causes of Hyponatremia

Hyponatremia in patients with kidney disease or heart failure results primarily from impaired free water excretion due to elevated antidiuretic hormone (ADH) levels, combined with neurohormonal activation and medication effects.

Heart Failure-Related Hyponatremia

• Reduced cardiac output leads to decreased renal perfusion, causing activation of the renin-angiotensin-aldosterone (RAA) system and increased ADH secretion, which promotes water retention and dilutional hyponatremia. 3

• Loop diuretics promote natriuresis by reducing sodium reabsorption via the NKCC transporter in the loop of Henle, resulting in sodium loss that can contribute to hyponatremia when combined with water retention. 3

• Thiazide diuretics inhibit the sodium-chloride transporter in the distal tubule and can cause hyponatremia through increased sodium excretion and impaired free water clearance. 3

Kidney Disease-Related Hyponatremia

• Impaired renal function reduces the kidney's ability to excrete free water, particularly when GFR is significantly reduced. 3

• Diuretic-induced natriuresis causes upregulation of sodium epithelial channels (ENaC), which is aldosterone-sensitive, leading to further sodium loss. 3

• Metabolic alkalosis can be aggravated in renal failure because of impaired acid-base homeostasis, which can accompany hyponatremia. 3

Medication-Induced Hyponatremia

• Thiazide diuretics are particularly associated with hyponatremia due to their effects on the distal tubule and impaired diluting capacity. 3

• ACE inhibitors and ARBs can contribute to hyponatremia through their effects on the RAA system, though this is less common than hyperkalemia. 3

Dietary and Lifestyle Factors

• Increased sodium consumption during travel or eating out can paradoxically worsen fluid retention in heart failure patients, though this typically causes hypervolemic hyponatremia rather than true sodium depletion. 3

• Patients at risk of hyponatremia require careful management of sodium and volume balance, particularly those with cardiorenal syndrome treated with RAAS inhibitors. 3

Clinical Context

• Both the absolute sodium level and the rate of decline determine clinical significance—rapid decreases are more likely to cause neurological symptoms than gradual declines over weeks. 4

• Symptomatic patients, those likely to require saline therapy, and those with acute and transient hyponatremia associated with head trauma or postoperative state require different management than chronic hyponatremia. 4