What causes elevated Blood Urea Nitrogen (BUN) levels?

Causes of Elevated Blood Urea Nitrogen (BUN)

Elevated BUN results from either decreased renal clearance or increased urea production, with primary causes including renal dysfunction, volume depletion, heart failure, increased protein catabolism, gastrointestinal bleeding, and high protein intake. 1

Pathophysiologic Mechanisms

Decreased Renal Clearance

• Acute kidney injury reduces glomerular filtration rate, leading to decreased urea clearance 1
• Heart failure causes reduced cardiac output, decreasing renal perfusion, while neurohormonal activation promotes fluid retention and renal vasoconstriction 1
• BUN is particularly sensitive to volume status because 40-50% of filtered urea is reabsorbed in the proximal tubule, paralleling sodium and water reabsorption 1
• This reabsorption characteristic makes BUN more sensitive to hemodynamic changes than creatinine 1

Increased Urea Production

• High protein intake (>100 g/day) increases hepatic urea production 2
• Gastrointestinal bleeding provides a large protein load from digested blood 2
• Increased protein catabolism occurs with sepsis, high-dose corticosteroids, severe illness, or hypercatabolic states 2
• Hypoalbuminemia (<2.5 g/dL) is frequently associated with disproportionate BUN elevation 2

Clinical Categories of Elevated BUN

Pre-Renal Azotemia

• Volume depletion from excessive diuresis, inadequate fluid intake, or gastrointestinal losses 3
• Reduced cardiac output from heart failure or shock states 2
• Hypovolemic or septic shock with systemic hypoperfusion 2
• Fractional sodium excretion <1% supports pre-renal azotemia, though this finding is present in only a minority of cases with disproportionate BUN elevation 2

Renal Causes

• Intrinsic kidney disease with reduced GFR 1
• Renal artery stenosis causing decreased renal perfusion 4
• Drug-induced renal dysfunction, particularly with ACE inhibitors, ARBs, or NSAIDs 5, 4

Post-Renal Causes

• Urinary retention from bladder emptying disorders, prostatic hyperplasia, or urethral narrowing can cause acute elevation when diuretics increase urine production 3

Disproportionate BUN Elevation (BUN:Creatinine Ratio >20:1)

When BUN rises disproportionately to creatinine, multiple factors are typically present rather than simple pre-renal azotemia. 2

Common Contributing Factors

• Elderly patients are particularly susceptible due to lower muscle mass and reduced creatinine production 2
• Multiple concurrent factors are present in 84% of cases with massive BUN elevation (>100 mg/dL with creatinine <5 mg/dL) 2
• High mortality (58% in one ICU series) reflects severe underlying illness rather than the BUN elevation itself 2
• Infection and sepsis are present in 74% of cases with disproportionate elevation 2

Medication-Related Causes

• Diuretics (furosemide) cause volume depletion and increased proximal tubular reabsorption of urea 3
• ACE inhibitors and ARBs can cause BUN elevation through hemodynamic effects on glomerular filtration, with increases up to 50% above baseline considered acceptable 5, 4
• Corticosteroids increase protein catabolism 2

Prognostic Significance

BUN has independent prognostic value beyond creatinine-based estimates of kidney function. 6, 7

• In heart failure, BUN is a better predictor of outcomes than creatinine or estimated GFR, reflecting both cardiac and renal dysfunction as well as neurohormonal activation 1
• BUN >28 mg/dL is independently associated with mortality in critically ill ICU patients, even after correction for APACHE2 scores and creatinine 8
• Elevated BUN predicts mortality in acute coronary syndromes independent of creatinine-based GFR estimates, particularly in patients with normal to mildly reduced kidney function 7
• Higher BUN/creatinine ratio is associated with worse outcomes in chronic heart failure across the spectrum of ejection fractions, independent of GFR and NT-proBNP 6

Laboratory Considerations and Pitfalls

Sampling Errors

• Dilution of blood sample with saline reduces measured BUN concentration 5
• Drawing sample after dialysis has started lowers BUN through solute removal 5
• Laboratory calibration errors can affect accuracy 5
• Timing of sample collection is critical for accurate assessment 5

Monitoring Recommendations

• Serum electrolytes, CO2, creatinine, and BUN should be determined frequently during the first few months of diuretic or ACE inhibitor therapy and periodically thereafter 3
• Reversible elevations of BUN may occur with dehydration and should be avoided, particularly in patients with renal insufficiency 3