What are the causes of refractory hyperkalemia?

Causes of Refractory Hyperkalemia

Refractory hyperkalemia occurs when potassium levels remain elevated despite standard treatment, most commonly due to advanced kidney disease, continued use of RAAS inhibitors, inadequate dialysis in dialysis-dependent patients, or unrecognized ongoing potassium sources. 1

Primary Mechanisms Leading to Refractory Hyperkalemia

Impaired Renal Potassium Excretion

• Advanced chronic kidney disease (CKD stage 4-5) is the most common cause, with up to 73% of patients developing hyperkalemia due to severely reduced glomerular filtration rate 2
• Acute kidney injury (AKI) was present in all cases of hyperkalemia-induced cardiac arrest in one retrospective study, often accompanied by acute pancreatitis or hepatic failure 3
• Inadequate dialysis in dialysis-dependent patients represents a critical but often overlooked cause of persistent hyperkalemia 1

Medication-Related Causes

• RAAS inhibitors (ACE inhibitors, ARBs, direct renin inhibitors, mineralocorticoid receptor antagonists) are the most important drug class causing hyperkalemia by reducing aldosterone-mediated potassium excretion 3, 4
• Combination RAAS therapy increases hyperkalemia risk to 5-10% in patients with heart failure or CKD, compared to <2% with monotherapy 3
• NSAIDs reduce renal potassium excretion and are commonly overlooked as contributing factors 1, 4
• Potassium-sparing diuretics (spironolactone, triamtereno, amilorida) directly impair renal potassium elimination 5
• Calcineurin inhibitors (cyclosporine, tacrolimus), heparin and derivatives, trimethoprim-sulfamethoxazol, and beta-blockers all contribute through various mechanisms 5, 4

Transcellular Potassium Shifts

• Metabolic acidosis from sepsis or infection shifts potassium from intracellular to extracellular space 1, 5
• Hyperglycemia causes transcellular potassium shifts due to hyperosmolarity and insulin deficiency 5
• Tissue destruction from trauma, rhabdomyolysis, or tumor lysis releases intracellular potassium stores 1

Endocrine Disorders

• Aldosterone deficiency (hypoaldosteronism, Addison's disease) impairs renal potassium excretion 3, 1
• Diabetes mellitus increases risk through multiple mechanisms including hyporeninemic hypoaldosteronism 1, 2

Contributing Factors Often Missed

Dietary and Supplemental Sources

• Continued high potassium intake (>3 g/day) from bananas, oranges, potatoes, tomatoes, salt substitutes, legumes, chocolate, and certain herbal supplements 1, 5
• Potassium-containing medications and supplements that are not discontinued 4
• Stored blood products can release significant potassium during transfusion 3

Gastrointestinal Factors

• Constipation reduces fecal potassium elimination and is frequently overlooked 1
• Inadequate response to potassium binders (sodium polystyrene sulfonate) due to poor efficacy or intolerance 6

Clinical Context Issues

• Pseudohyperkalemia from hemolysis during phlebotomy or tissue breakdown must be ruled out before escalating treatment 1, 5
• Rebound hyperkalemia occurs 2-4 hours after temporary measures (insulin, albuterol, bicarbonate) wear off, as these agents do not increase potassium excretion 3

High-Risk Patient Populations

Patients with multiple comorbidities face compounding risk:

• Advanced CKD combined with heart failure and diabetes creates up to 40% risk of hyperkalemia 2
• Elderly patients on multiple RAAS inhibitors with declining renal function 2
• Heart failure patients requiring MRAs, where up to one-third develop hyperkalemia >5.0 mEq/L 3

Critical Diagnostic Steps to Identify Refractory Causes

• Measure serum creatinine and calculate eGFR to assess degree of renal impairment, as kidney disease is the most common underlying cause 5
• Systematically review ALL medications including over-the-counter NSAIDs, herbal supplements, and salt substitutes 1, 5
• Assess for metabolic acidosis which both causes and perpetuates hyperkalemia 1, 7
• Evaluate dialysis adequacy in dialysis-dependent patients 1
• Check for constipation and ensure adequate bowel function 1
• Rule out pseudohyperkalemia by repeating measurement with proper technique or arterial sample 1, 5

Common Pitfalls Leading to Refractory Hyperkalemia

• Failing to discontinue or reduce RAAS inhibitors when potassium exceeds 6.0 mmol/L, though permanent discontinuation should be avoided in favor of dose reduction plus potassium binders 3, 1
• Not recognizing that temporary measures (insulin, albuterol, bicarbonate) only last 1-4 hours and must be followed by definitive potassium removal strategies 3
• Overlooking NSAIDs as a contributing medication, particularly in patients with pain or infection 1
• Inadequate use of loop diuretics in patients with preserved renal function who could benefit from enhanced urinary potassium excretion 3, 7
• Excessive dietary potassium restriction without addressing medication causes or using newer potassium binders 7