What are the causes of hyperkalemia and hypercalcemia?

Causes of Hyperkalemia and Hypercalcemia

The most common causes of hyperkalemia include chronic kidney disease, medications (particularly RAASi therapy), and excessive potassium intake, while hypercalcemia is most commonly caused by hyperparathyroidism, malignancy, and medication side effects including calcium-containing potassium binders. 1, 2

Causes of Hyperkalemia

Renal Causes

• Chronic kidney disease (CKD): Risk increases progressively as eGFR decreases, becoming significant when eGFR falls below 60 mL/min/1.73m² and particularly high when below 15 mL/min/1.73m² 1
• Acute kidney injury (AKI): Decreased tubular flow rate reduces potassium secretion 3
• Hyporeninemic hypoaldosteronism: Diminished aldosterone leads to decreased potassium secretion 3

Medication-Related Causes

• Renin-angiotensin-aldosterone system inhibitors (RAASi): ACE inhibitors, ARBs, and aldosterone antagonists (e.g., spironolactone) 1
• Potassium-sparing diuretics: Spironolactone, eplerenone, amiloride, triamterene 2
• Other medications:
  • NSAIDs
  • Beta-blockers
  • Calcineurin inhibitors (cyclosporine, tacrolimus)
  • Heparin
  • Trimethoprim
  • Pentamidine 1

Other Causes

• Excessive potassium intake: Dietary sources, salt substitutes, potassium supplements 1
• Transcellular shifts:
  • Metabolic acidosis
  • Insulin deficiency/hyperglycemia
  • Cell lysis (tumor lysis syndrome, rhabdomyolysis, hemolysis)
  • Tissue destruction (burns, trauma, surgery) 1, 4
• Constipation: Particularly in CKD patients 1

Causes of Hypercalcemia

Primary Causes

• Primary hyperparathyroidism: Excessive PTH secretion from parathyroid glands 1
• Malignancy-related:
  • Solid tumors with bone metastases
  • Humoral hypercalcemia of malignancy (PTH-related protein)
  • Multiple myeloma 5

Medication-Related Causes

• Calcium-containing potassium binders: Calcium polystyrene sulfonate can cause hypercalcemia, especially in CKD patients 6, 7
• Vitamin D excess: Supplementation or medications containing vitamin D 1, 5
• Thiazide diuretics: Decrease urinary calcium excretion 8
• Other medications:
  • Lithium
  • Estrogen
  • Calcipotriene
  • Teriparatide 8

Other Causes

• Granulomatous disorders: Sarcoidosis, tuberculosis 5
• Immobilization: Especially in patients with high bone turnover
• Milk-alkali syndrome: Excessive intake of calcium and absorbable alkali
• Familial hypocalciuric hypercalcemia: Genetic disorder affecting calcium sensing
• Adrenal insufficiency: Reduced cortisol production 5

Clinical Manifestations

Hyperkalemia

• ECG changes (progressive with increasing severity):
  • Peaked T waves (>5.5 mmol/L)
  • Prolonged PR interval, flattened P waves (6.5-7.5 mmol/L)
  • Widened QRS complex (7.0-8.0 mmol/L)
  • Sine wave pattern, ventricular fibrillation, asystole (>10 mmol/L) 1, 2
• Neuromuscular symptoms: Paresthesias, weakness, flaccid paralysis 1

Hypercalcemia

• Neurological: Confusion, lethargy, fatigue
• Gastrointestinal: Nausea, vomiting, constipation, abdominal pain
• Renal: Polyuria, polydipsia, kidney stones, acute kidney injury 5
• Cardiac: Shortened QT interval, bradycardia, heart block 1

Special Considerations

Concurrent Hyperkalemia and Hypercalcemia

• Calcium-containing potassium binders (e.g., calcium polystyrene sulfonate) used to treat hyperkalemia can cause hypercalcemia, especially in CKD patients 6, 7
• Patients with CKD are at risk for both disorders due to impaired excretion of both electrolytes 1, 3
• Acute kidney injury can be both a cause and consequence of hypercalcemia 5

Management Pitfalls

• Treating hyperkalemia with calcium-containing agents in patients already at risk for hypercalcemia
• Failing to monitor calcium levels in patients on calcium polystyrene sulfonate
• Discontinuing essential medications (like RAASi) without attempting other management strategies first 1, 2
• Overlooking transcellular shifts as causes, which can lead to rebound electrolyte disturbances after initial treatment 4

Diagnostic Approach

1. Verify true electrolyte abnormality (rule out pseudohyperkalemia from hemolysis)
2. Assess severity through laboratory values and ECG findings
3. Review medication list for potential causes
4. Evaluate kidney function (eGFR, creatinine)
5. Consider underlying conditions (malignancy, endocrine disorders)
6. Check for concurrent electrolyte abnormalities

By understanding these causes, clinicians can better diagnose and manage these potentially life-threatening electrolyte disorders.