9.1 Acute Kidney Injury: Staging, Etiology & Urine Microscopy
Key Takeaways
- Hypotension-induced injury, toxic injury, rhabdomyolysis, hepatorenal syndrome, disseminated atheroembolism and myeloma-induced kidney disease are enumerated under acute kidney injury.
- Muddy brown granular casts indicate acute tubular necrosis, while bland sediment with concentrated urine suggests prerenal physiology.
- Fractional excretion of sodium is uninterpretable after diuretic administration, where the fractional excretion of urea is used instead.
- White cell casts with eosinophiluria and a temporally related drug exposure suggest acute interstitial nephritis, for which drug withdrawal is the primary treatment.
- Cholesterol embolization after vascular instrumentation causes livedo reticularis, blue toes, eosinophilia and low complement with a subacute rise in creatinine.
Acute kidney injury (AKI) and glomerular disorders represent core competencies on the ABIM Internal Medicine certification exam. Mastery of acute azotemia requires distinguishing hemodynamic prerenal states from intrinsic parenchymal injury (such as acute tubular necrosis and acute interstitial nephritis), interpreting urinary indices and sediment microscopy, differentiating nephrotic from nephritic syndromes, and recognizing life-threatening complications that demand emergent renal replacement therapy.
1. KDIGO Staging & Classification of Acute Kidney Injury
The Kidney Disease: Improving Global Outcomes (KDIGO) consensus criteria define AKI by acute changes in serum creatinine (SCr) or oliguria. Staging stratifies disease severity, predicts in-hospital mortality, and guides the timing of nephrology consultation and renal replacement therapy.
KDIGO Staging Criteria
| Stage | Serum Creatinine (SCr) Criteria | Urine Output (UOP) Criteria |
|---|---|---|
| Stage 1 | SCr 1.5–1.9 times baseline OR >=0.3 mg/dL (>=26.5 µmol/L) increase within 48 hours | <0.5 mL/kg/h for 6 to 12 hours |
| Stage 2 | SCr 2.0–2.9 times baseline | <0.5 mL/kg/h for >=12 hours |
| Stage 3 | SCr >=3.0 times baseline OR SCr >=4.0 mg/dL (>=353.6 µmol/L) with acute rise >=0.5 mg/dL OR Initiation of Renal Replacement Therapy (RRT) OR in patients <18y, decrease in eGFR to <35 mL/min/1.73m2 | <0.3 mL/kg/h for >=24 hours OR Anuria for >=12 hours |
Clinical Pearl — Baseline Creatinine Identification: When baseline serum creatinine is unknown, use the lowest stable value documented within the preceding 3 to 12 months. In oliguric patients who receive aggressive IV fluid resuscitation, dilutional decrease in serum creatinine can mask the true severity of AKI; always account for positive fluid balance.
2. Diagnostic Evaluation: Prerenal Azotemia vs. Acute Tubular Necrosis (ATN)
Determining whether an acute decline in GFR is due to renal hypoperfusion (prerenal azotemia) or ischemic/nephrotoxic tubular cell death (acute tubular necrosis) is the primary diagnostic challenge in hospitalized patients.
Diagnostic Urinary Indices
-
Fractional Excretion of Sodium (FeNa):
- FeNa < 1%: Suggests intact tubular reabsorption of sodium in response to decreased renal perfusion (prerenal azotemia).
- FeNa > 2%: Suggests tubular epithelial cell injury with loss of sodium-reabsorbing capacity (ATN).
- FeNa Limitations & Exceptions: FeNa can be <1% in ATN caused by iodinated radiocontrast nephropathy, rhabdomyolysis/myoglobinuria, acute glomerulonephritis, and severe sepsis with renal vasoconstriction. FeNa can be >1% in prerenal azotemia if the patient has received diuretic therapy within the preceding 24–48 hours or has pre-existing CKD with salt-wasting.
-
Fractional Excretion of Urea (FeUrea):
- Primary Indication: Essential when a patient is receiving loop diuretics (e.g., Furosemide, Bumetanide), because loop diuretics block Na+/K+/2Cl- cotransporters in the thick ascending limb, artificially elevating urine sodium and FeNa.
- FeUrea < 35%: Strongly indicates prerenal azotemia (urea reabsorption in the proximal tubule is passive and enhanced by hypovolemia, independent of loop diuretic actions in the loop of Henle).
- FeUrea > 50%: Indicates ATN.
Comparative Diagnostic Matrix
| Diagnostic Parameter | Prerenal Azotemia | Acute Tubular Necrosis (ATN) | Acute Interstitial Nephritis (AIN) | Acute Glomerulonephritis (GN) |
|---|---|---|---|---|
| BUN : Serum Cr Ratio | >20 : 1 (avid urea reabsorption) | 10–15 : 1 | 10–15 : 1 | >20 : 1 (in severe oliguria) |
| Urine Sodium (UNa) | <20 mEq/L | >40 mEq/L | Variable (>20–40 mEq/L) | <20 mEq/L |
| Urine Osmolality | >500 mOsm/kg (concentrated) | <350 mOsm/kg (isosthenuric) | <350–400 mOsm/kg | >500 mOsm/kg |
| FeNa | <1% | >2% | Variable (>1%) | <1% |
| FeUrea (on diuretics) | <35% | >50% | >50% | <35% |
| Urine Sediment Microscopy | Normal, hyaline casts | Muddy brown granular casts, renal tubular epithelial (RTE) cells | WBC casts, WBCs, eosinophiluria | Dysmorphic RBCs (acanthocytes), RBC casts, sub-nephrotic proteinuria |
3. Urine Microscopy & Cast Typology
Microscopic examination of fresh, uncentrifuged or gently centrifuged urine sediment is the most cost-effective diagnostic tool in nephrology.
- Muddy Brown Granular Casts / RTE Cell Casts: Pathognomonic for Acute Tubular Necrosis (ATN). Formed by sloughed necrotic tubular epithelial cells that degenerate into coarse, dark granular debris embedded within Tamm-Horsfall mucoprotein.
- WBC Casts & Eosinophiluria: Hallmark of Acute Interstitial Nephritis (AIN). WBC casts confirm renal parenchymal inflammation (differentiating AIN or pyelonephritis from lower urinary tract cystitis). Eosinophiluria is visualized with Hansel or Wright stain (>1% eosinophils); however, its sensitivity and specificity are poor (frequently absent in biopsy-proven AIN).
- Dysmorphic RBCs & RBC Casts: Diagnostic of Glomerulonephritis (GN) or vasculitis. Glomerular red blood cells undergo mechanical and osmotic shear stress across a disrupted glomerular basement membrane, producing acanthocytes (ring-shaped RBCs with vesicle-like blebs / "Mickey Mouse ears").
- Broad Waxy Casts: Indicative of Advanced Chronic Kidney Disease (CKD) with dilated, atrophic, sclerotic tubules with low flow.
- Hyaline Casts: Composed purely of Tamm-Horsfall mucoprotein; seen in concentrated urine, prerenal azotemia, strenuous exercise, or normal states.
- Fatty Casts & Oval Fat Bodies ("Maltese Cross"): Highly characteristic of Nephrotic Syndrome. Tubular cells engorged with reabsorbed filtered cholesterol and lipoproteins produce polarized light birefringence.
- Crystals:
- Envelope / Dumbbell: Calcium oxalate (ethylene glycol poisoning, hyperoxaluria).
- Needle / Rhomboid: Uric acid (acute urate nephropathy in tumor lysis syndrome).
- Coffin-lid: Triple phosphate / struvite (Proteus, Klebsiella urosepsis).
- Hexagonal: Cystinuria.
4. Acute Interstitial Nephritis (AIN)
Acute interstitial nephritis is an immune-mediated tubulointerstitial inflammation causing acute renal dysfunction.
Etiologies
- Medications (>75% of cases):
- Antibiotics: Penicillins (methicillin, ampicillin), cephalosporins, fluoroquinolones (ciprofloxacin), sulfonamides, rifampin, vancomycin.
- Proton Pump Inhibitors (PPIs): Omeprazole, pantoprazole, esomeprazole (frequently insidious onset weeks to months after starting therapy without overt systemic allergic features).
- NSAIDs & COX-2 Inhibitors: Often presents uniquely as AIN combined with nephrotic-range proteinuria (due to concurrent minimal change-like podocyte effacement).
- Immune Checkpoint Inhibitors (ICIs): Pembrolizumab, nivolumab, ipilimumab (delayed onset after multiple cycles, mediated by T-cell reactivation).
- Infections (5–10%): Legionella, Leptospira, CMV, EBV, HIV, Streptococcus.
- Autoimmune / Systemic Diseases (10–15%): Sarcoidosis, Sjögren syndrome, Systemic Lupus Erythematosus, Tubulointerstitial Nephritis and Uveitis (TINU syndrome).
Clinical Presentation & Workup
- The Classic Triad: Low-grade fever, maculopapular morbilliform rash, and peripheral eosinophilia is present in <30% of patients. Do not exclude AIN based on the absence of this triad!
- Laboratory Findings: Progressive rise in serum creatinine, sterile pyuria, WBC casts, mild non-nephrotic proteinuria (<1–2 g/day; except NSAID-induced), and elevated serum IgE.
- Definitive Diagnosis: Percutaneous Renal Biopsy is the gold standard, demonstrating diffuse interstitial edema, dense inflammatory infiltration (T-lymphocytes, monocytes, plasma cells, and eosinophils), and tubulitis.
- Management Strategy:
- Immediate Cessation of Offending Agent: The single most important therapeutic maneuver.
- Systemic Corticosteroids: Indicated if serum creatinine fails to improve within 3 to 5 days of drug withdrawal, or if severe renal failure/biopsy-confirmed extensive interstitial inflammation is present. Regimen: Oral Prednisone 1 mg/kg/day (maximum 60–80 mg/day) for 2 to 4 weeks, followed by a gradual taper over 4 to 6 weeks. Early initiation within 7–14 days of onset prevents irreversible chronic interstitial fibrosis.
A 68-year-old man with a history of heart failure with reduced ejection fraction on Furosemide 80 mg PO BID and Lisinopril 20 mg daily is admitted with severe gastroenteritis and poor oral intake. Over 48 hours, his blood pressure drops from 128/76 mmHg to 98/62 mmHg, and his serum creatinine increases from a baseline of 1.1 mg/dL to 3.2 mg/dL. Urinalysis demonstrates specific gravity 1.028, trace protein, and bland sediment with few hyaline casts. Spot urine chemistry reveals Urine Sodium 48 mEq/L, Urine Creatinine 110 mg/dL, Urine Urea Nitrogen 420 mg/dL, and Serum BUN 64 mg/dL. Which diagnostic finding best distinguishes the mechanism of this patient's acute kidney injury?