What are the steps for differential diagnosis and management of hyperkalemia?

Differential Diagnosis of Hyperkalemia

The differential diagnosis of hyperkalemia requires a systematic approach categorizing causes into three pathophysiologic mechanisms: increased potassium intake, transcellular shift from intracellular to extracellular space, and decreased renal excretion—with the critical first step being exclusion of pseudo-hyperkalemia from hemolysis or improper blood sampling. 1, 2

Step 1: Exclude Pseudo-Hyperkalemia

Before pursuing any workup, repeat the potassium measurement with proper technique or obtain an arterial sample if pseudo-hyperkalemia is suspected. 1, 2

• Pseudo-hyperkalemia results from potassium release during blood collection from hemolysis, repeated fist clenching, or prolonged tourniquet application 1, 2
• If hemolysis is present on the lab report, determine whether it occurred in the test tube or represents true in vivo hemolysis 1
• This is a critical pitfall—aggressive treatment of pseudo-hyperkalemia can cause life-threatening hypokalemia 2

Step 2: Assess Severity and Urgency

Classify hyperkalemia severity: mild (5.0-5.5 mEq/L), moderate (5.5-6.0 mEq/L), or severe (≥6.0 mEq/L), and immediately obtain an ECG regardless of potassium level. 1

• ECG changes (peaked T waves, flattened P waves, prolonged PR interval, widened QRS) indicate urgent treatment regardless of the absolute potassium value 2, 3
• However, ECG findings are highly variable and less sensitive than laboratory values—their absence does not exclude dangerous hyperkalemia 2
• Patients with chronic kidney disease, diabetes, or heart failure may tolerate potassium levels up to 6.0 mEq/L without arrhythmias due to compensatory mechanisms 1

Step 3: Categorize by Mechanism

A. Increased Potassium Intake (Least Common)

Review dietary sources and supplements, though intake alone rarely causes hyperkalemia in patients with normal renal function. 1

• Potassium supplements and salt substitutes (DASH diet products) 1
• High-potassium foods: bananas, melons, orange juice 1
• Herbal supplements: alfalfa, dandelion, hawthorne berry, horsetail, nettle, noni juice, Siberian ginseng 1
• Stored blood products during massive transfusion 1

B. Transcellular Shift (Redistribution)

Identify conditions causing potassium movement from intracellular to extracellular space. 1

• Metabolic acidosis: Each 0.1 decrease in pH increases potassium by approximately 0.6 mEq/L 1
• Insulin deficiency or hyperglycemia: Common in diabetic ketoacidosis 1
• Tissue breakdown: Rhabdomyolysis, tumor lysis syndrome, massive hemolysis, severe burns 1, 4
• Medications causing shift: Succinylcholine, digitalis toxicity, beta-blockers (non-selective) 1

C. Decreased Renal Excretion (Most Common)

This is the predominant mechanism in clinical practice, occurring in 77% of hospitalized cases. 5

Renal Failure

• Acute kidney injury (AKI): Particularly dangerous in patients with previously normal renal function—this population has higher mortality than those with chronic kidney disease 6
• Chronic kidney disease: Risk increases progressively as eGFR decreases, occurring in up to 73% of patients with advanced CKD 1

Medications Impairing Renal Excretion (Present in 63% of Cases)

Conduct a comprehensive medication review focusing on these drug classes: 1, 5

• RAAS inhibitors: ACE inhibitors, ARBs, mineralocorticoid receptor antagonists (spironolactone, eplerenone), direct renin inhibitors (aliskiren), sacubitril/valsartan 1
• Potassium-sparing diuretics: Amiloride, triamterene 1
• NSAIDs: Reduce aldosterone secretion and impair renal potassium excretion 1
• Immunosuppressants: Cyclosporine, tacrolimus (calcineurin inhibitors) 1
• Antimicrobials: Trimethoprim-sulfamethoxazole, pentamidine 1
• Anticoagulants: Heparin (suppresses aldosterone) 1
• Others: Beta-blockers, mannitol, penicillin G 1

Endocrine Disorders

• Hyporeninemic hypoaldosteronism: Common in diabetic nephropathy 7
• Addison's disease: Primary adrenal insufficiency 4
• Type IV renal tubular acidosis: Associated with diabetes and chronic interstitial nephritis 4

Step 4: Obtain Diagnostic Laboratory Tests

Order urine potassium, creatinine, and osmolarity as the first step in determining the underlying cause. 7

• Urine potassium >20 mEq/L: Suggests extrarenal causes (transcellular shift, increased intake) 7, 4
• Urine potassium <20 mEq/L: Indicates renal potassium retention (renal failure, hypoaldosteronism, medications) 7, 4
• Transtubular potassium gradient (TTKG): Can help differentiate renal from extrarenal causes when interpretation is unclear 4
• Additional tests: Serum creatinine, BUN, glucose, arterial blood gas (to assess for acidosis), cortisol and aldosterone levels if endocrine disorder suspected 4

Step 5: Identify High-Risk Patient Populations

Recognize that certain populations have substantially increased risk and require more aggressive monitoring. 1

• Advanced chronic kidney disease (eGFR <30 mL/min/1.73 m²) 1
• Heart failure, particularly those on RAAS inhibitors 1
• Diabetes mellitus, especially with diabetic nephropathy 1
• Recent myocardial infarction 1
• Advanced age (>65 years) 1
• Patients on multiple medications affecting potassium homeostasis 1

Critical Management Principle

In patients with cardiovascular disease on RAAS inhibitors who develop hyperkalemia, prioritize maintaining these life-saving medications by initiating potassium-lowering agents rather than discontinuing therapy, as RAAS inhibitors reduce mortality and morbidity. 1, 2

• For potassium >5.0 mEq/L: Initiate approved potassium-lowering agent (patiromer or sodium zirconium cyclosilicate) and maintain RAAS inhibitor unless alternative treatable cause identified 2, 3
• For potassium >6.5 mEq/L: Temporarily discontinue or reduce RAAS inhibitor, initiate potassium-lowering agent, and monitor closely with plan to reinitiate RAAS therapy after stabilization 2, 3
• Check potassium levels 7-10 days after starting or increasing RAAS inhibitor doses 2

Common Pitfalls to Avoid

• Do not treat pseudo-hyperkalemia aggressively—always confirm with repeat measurement 1, 2
• Do not rely solely on ECG findings—they are variable and less sensitive than laboratory values 2
• Do not discontinue RAAS inhibitors permanently in patients with cardiovascular disease without attempting potassium-lowering strategies first 1, 2
• Do not overlook medication-induced hyperkalemia—present in 63% of hospitalized cases and often reversible 5
• Do not assume chronic kidney disease patients tolerate hyperkalemia well—while they may have adaptive mechanisms, mortality risk remains significant, particularly with acute-on-chronic kidney injury 1, 6