How do you interpret BUN (Blood Urea Nitrogen)/creatinine ratio, urine sodium, and FENa (Fractional Excretion of Sodium) in patients with suspected acute kidney injury (AKI)?

Interpretation of Laboratory Values in Acute Kidney Injury

BUN/Creatinine Ratio

A BUN:Cr ratio >20:1 classically suggests prerenal azotemia, while ratios ≤20:1 point toward intrinsic kidney disease, though this marker has significant limitations and should never be used in isolation. 1

• The BUN:Cr ratio reflects differential handling of urea versus creatinine by the kidney in response to perfusion changes 1
• In prerenal states, enhanced proximal tubular reabsorption of urea (driven by increased aldosterone and angiotensin II) elevates BUN disproportionately to creatinine 2
• Ratios between 15-20:1 fall in a gray zone and require integration with other clinical parameters 1
• Critical caveat: This ratio is heavily influenced by non-renal factors including protein intake, gastrointestinal bleeding, corticosteroid use, and catabolic states, limiting its diagnostic utility 3

Urine Sodium and Fractional Excretion of Sodium (FENa)

FENa <1% suggests prerenal AKI with intact tubular function and appropriate sodium conservation, while FENa >1% typically indicates intrinsic kidney injury, particularly acute tubular necrosis. 1, 4

Diagnostic Performance of FENa

• FENa demonstrated correct diagnostic classification in 86 of 87 patients with acute renal failure in prospective analysis, outperforming urine osmolality, urine sodium concentration, and U/P creatinine ratio 4
• In prerenal AKI, FENa is typically <1% because tubular function remains intact and responds appropriately to decreased perfusion through enhanced sodium reabsorption 2
• FENa >1% reliably identifies acute tubular necrosis, non-oliguric ATN, and urinary tract obstruction 4

Critical Limitations of FENa

• In cirrhosis, FENa <1% has 100% sensitivity but only 14% specificity for prerenal causes, meaning many patients with intrinsic kidney disease can also have low FENa 1, 2
• Patients receiving diuretics can have low FENa despite intrinsic kidney injury, rendering this test unreliable in this common clinical scenario 5, 6
• Low FENa (<1%) was only seen in 44.4% of prerenal failure patients in pediatric studies, limiting sensitivity 7

Fractional Excretion of Urea (FEUrea) as Alternative

When diuretics have been administered, FEUrea <35% should be used instead of FENa to assess for prerenal physiology, as it is less affected by diuretic therapy. 1, 8

• FEUrea <35% had 77.8% sensitivity for prerenal failure versus 44.4% for FENa <1% in pediatric populations 7
• In hepatorenal syndrome, FEUrea <28% demonstrated 75% sensitivity and 83% specificity for differentiating HRS from non-HRS causes 1
• However, recent meta-analysis shows FEUrea has limited overall utility with pooled sensitivity of only 66% and specificity of 75% for distinguishing intrinsic from prerenal AKI 8
• In patients on diuretics, FEUrea demonstrated lower sensitivity (52%) but higher specificity (82%) compared to FENa for diagnosing intrinsic AKI 8

Combined Interpretation Strategy

• In early sepsis, the combination of high FENa and high FEUrea is strongly predictive (94.5% negative predictive value) of transient AKI, while high FENa with low FEUrea suggests intrinsic AKI 6
• Low FENa (<1%) and low FEUrea (<35%) is highly prevalent (77.3% and 63.2% respectively) in the first hours of sepsis, regardless of ultimate AKI trajectory 6

Urea as Surrogate Marker for Renal Perfusion

Urea serves as a surrogate for renal perfusion because its reabsorption is directly influenced by tubular flow rate and neurohormonal activation in response to decreased effective arterial blood volume. 2

Physiological Basis

• Decreased renal perfusion activates the renin-angiotensin-aldosterone system, sympathetic nervous system, and arginine vasopressin 2
• Increased aldosterone and angiotensin II stimulate enhanced sodium and water reabsorption in the proximal tubule 2
• Slower tubular flow rates allow more time for passive urea reabsorption along its concentration gradient 2
• This results in disproportionate elevation of BUN relative to creatinine in prerenal states 2

Clinical Application

• Urea reabsorption is primarily dependent on passive forces, making it less affected by many confounding variables that influence sodium handling 7
• The kidney's ability to concentrate urea reflects intact tubular function responding to perfusion pressure 2

Urine Microscopy Findings

Urine sediment analysis should be performed routinely in all AKI cases despite being underutilized, as specific findings can definitively establish the diagnosis and guide management. 3

Muddy Brown Casts

• Muddy brown granular casts are pathognomonic for acute tubular necrosis and indicate tubular epithelial cell injury and necrosis 9
• Microscopy score for casts and tubular cells showed approximately three-fold increase in adjusted risk for worsening AKI or death when comparing upper versus lower values 9
• Microscopy significantly improved net reclassification when added to baseline clinical assessment on the first day of AKI diagnosis 9

RBC Casts

• RBC casts indicate glomerulonephritis or vasculitis and require immediate nephrology consultation and consideration of kidney biopsy 3
• Their presence should prompt evaluation for systemic autoimmune disease, anti-GBM disease, or ANCA-associated vasculitis 3

Other Findings

• Hyaline casts are non-specific and can be seen in concentrated urine from prerenal states 3
• White blood cell casts suggest acute interstitial nephritis or pyelonephritis 3
• Renal tubular epithelial cells indicate tubular injury but are less specific than muddy brown casts 9

Implementation Challenges

• Despite KDIGO 2012 guidelines recommending urine sediment analysis for differential diagnosis, it is not routinely performed in many centers 3
• Unregulated diagnostic tests like urine sediment require careful standardization and quality control, with local evaluation for correct performance and interpretation 3

Electrolyte Abnormalities in AKI

Hyperkalemia

Elevated potassium represents the most immediately life-threatening electrolyte abnormality in AKI, requiring urgent treatment when >6.0 mEq/L or when ECG changes are present. 3

• Hyperkalemia results from decreased GFR reducing potassium excretion combined with cellular shifts from metabolic acidosis 3
• Risk is amplified by medications (ACE inhibitors, ARBs, potassium-sparing diuretics, NSAIDs) that should be immediately discontinued 1
• Tissue breakdown, hemolysis, and hypercatabolism further contribute to potassium elevation 3

Metabolic Acidosis

Metabolic acidosis in AKI results from impaired renal acid excretion and reduced bicarbonate regeneration, typically manifesting as high anion gap acidosis when GFR falls below 20-30 mL/min. 3

• Accumulation of organic acids (sulfate, phosphate, hippurate) increases the anion gap 3
• Reduced ammonia production and impaired distal hydrogen ion secretion prevent acid buffering 3
• Severe acidosis (pH <7.1) can worsen hyperkalemia by promoting potassium shift from intracellular to extracellular compartments 3

Hyponatremia

Hyponatremia in AKI typically reflects impaired free water excretion rather than true sodium depletion, and must be interpreted in the context of volume status to guide appropriate management. 3

• Decreased GFR reduces water delivery to diluting segments of the nephron 3
• Non-osmotic vasopressin release in response to decreased effective arterial volume impairs free water clearance 3
• Critical distinction: Hyponatremia with volume depletion requires cautious isotonic fluid resuscitation, while hyponatremia with volume overload requires fluid restriction and diuresis 5
• Fluid overload itself is associated with increased mortality and may impact AKI diagnosis through effects on creatinine volume of distribution 3

Integrated Clinical Significance

• All nephrotoxic drugs including NSAIDs, ACE inhibitors, ARBs, and aminoglycosides should be withdrawn immediately when AKI is diagnosed 1
• Diuretics should be held or reduced pending volume status reassessment 1
• Medications require dosing adjustments based on reduced GFR to prevent accumulation and toxicity 3
• Daily reassessment of electrolytes and volume status is mandatory in persistent AKI 3